Molecular insights of exercise therapy in disease prevention and treatment.

Lee, I.-M. et al. Effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy. Lancet 380, 219–229 (2012).

pubmed: 22818936 pmcid: 3645500 doi: 10.1016/S0140-6736(12)61031-9

Knight, J. A. Physical inactivity: associated diseases and disorders. Ann. Clin. Lab. Sci. 42, 320–337 (2012).

Kyu, H. H. et al. Physical activity and risk of breast cancer, colon cancer, diabetes, ischemic heart disease, and ischemic stroke events: systematic review and dose-response meta-analysis for the Global Burden of Disease Study 2013. BMJ 354, i3857 (2016).

pubmed: 27510511 pmcid: 4979358 doi: 10.1136/bmj.i3857

Pate, R. R. et al. Physical activity and public health: a recommendation from the Centers for Disease Control and Prevention and the American College of Sports Medicine. JAMA 273, 402–407 (1995).

pubmed: 7823386 doi: 10.1001/jama.1995.03520290054029

Caspersen, C. J., Powell, K. E. & Christenson, G. M. Physical activity, exercise, and physical fitness: definitions and distinctions for health-related research. Public Health Rep. Wash. DC 1974 100, 126–131 (1985).

Gleeson, M. et al. The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. Nat. Rev. Immunol. 11, 607–615 (2011).

pubmed: 21818123 doi: 10.1038/nri3041

Kujala, U. M. Evidence on the effects of exercise therapy in the treatment of chronic disease. Br. J. Sports Med. 43, 550–555 (2009).

pubmed: 19406731 doi: 10.1136/bjsm.2009.059808

Pedersen, B. K. & Saltin, B. Exercise as medicine—evidence for prescribing exercise as therapy in 26 different chronic diseases. Scand. J. Med. Sci. Sports 25, 1–72 (2015).

pubmed: 26606383 doi: 10.1111/sms.12581

Heinonen, I. et al. Organ-specific physiological responses to acute physical exercise and long-term training in humans. Physiology 29, 421–436 (2014).

pubmed: 25362636 doi: 10.1152/physiol.00067.2013

McGee, S. L. & Hargreaves, M. Exercise adaptations: molecular mechanisms and potential targets for therapeutic benefit. Nat. Rev. Endocrinol. 16, 495–505 (2020).

pubmed: 32632275 doi: 10.1038/s41574-020-0377-1

Ruegsegger, G. N. & Booth, F. W. Health benefits of exercise. Cold Spring Harb. Perspect. Med. 8, a029694 (2018).

pubmed: 28507196 pmcid: 6027933 doi: 10.1101/cshperspect.a029694

Safdar, A., Saleem, A. & Tarnopolsky, M. A. The potential of endurance exercise-derived exosomes to treat metabolic diseases. Nat. Rev. Endocrinol. 12, 504–517 (2016).

pubmed: 27230949 doi: 10.1038/nrendo.2016.76

Safdar, A. & Tarnopolsky, M. A. Exosomes as mediators of the systemic adaptations to endurance exercise. Cold Spring Harb. Perspect. Med. 8, a029827 (2018).

pubmed: 28490541 pmcid: 5830902 doi: 10.1101/cshperspect.a029827

Chow, L. S. et al. Exerkines in health, resilience and disease. Nat. Rev. Endocrinol. 18, 273–289 (2022).

pubmed: 35304603 pmcid: 9554896 doi: 10.1038/s41574-022-00641-2

Jin, L., Diaz-Canestro, C., Wang, Y., Tse, M. A. & Xu, A. Exerkines and cardiometabolic benefits of exercise: from bench to clinic. EMBO Mol. Med. 16, 432–444 (2024).

pubmed: 38321233 pmcid: 10940599 doi: 10.1038/s44321-024-00027-z

Ashcroft, S. P., Stocks, B., Egan, B. & Zierath, J. R. Exercise induces tissue-specific adaptations to enhance cardiometabolic health. Cell Metab. 36, 278–300 (2024).

pubmed: 38183980 doi: 10.1016/j.cmet.2023.12.008

Li, V. L. et al. An exercise-inducible metabolite that suppresses feeding and obesity. Nature 606, 785–790 (2022).

pubmed: 35705806 pmcid: 9767481 doi: 10.1038/s41586-022-04828-5

Chen, H. et al. Exercise training maintains cardiovascular health: signaling pathways involved and potential therapeutics. Signal Transduct. Target. Ther. 7, 306 (2022).

pubmed: 36050310 pmcid: 9437103 doi: 10.1038/s41392-022-01153-1

Hojman, P., Gehl, J., Christensen, J. F. & Pedersen, B. K. Molecular mechanisms linking exercise to cancer prevention and treatment. Cell Metab. 27, 10–21 (2018).

pubmed: 29056514 doi: 10.1016/j.cmet.2017.09.015

Tian, D. & Meng, J. Exercise for prevention and relief of cardiovascular disease: prognoses, mechanisms, and approaches. Oxid. Med. Cell. Longev. 2019, 1–11 (2019).

Wang, Q. & Zhou, W. Roles and molecular mechanisms of physical exercise in cancer prevention and treatment. J. Sport Health Sci. 10, 201–210 (2021).

pubmed: 32738520 doi: 10.1016/j.jshs.2020.07.008

Chen, J., Zhou, R., Feng, Y. & Cheng, L. Molecular mechanisms of exercise contributing to tissue regeneration. Signal Transduct. Target. Ther. 7, 1–24 (2022).

pubmed: 34980881 pmcid: 8724278 doi: 10.1038/s41392-021-00710-4

Ji, S. et al. Cellular rejuvenation: molecular mechanisms and potential therapeutic interventions for diseases. Signal Transduct. Target. Ther. 8, 116 (2023).

pubmed: 36918530 pmcid: 10015098 doi: 10.1038/s41392-023-01343-5

Moreira, J. B. N., Wohlwend, M. & Wisløff, U. Exercise and cardiac health: physiological and molecular insights. Nat. Metab. 2, 829–839 (2020).

pubmed: 32807982 doi: 10.1038/s42255-020-0262-1

Gubert, C. & Hannan, A. J. Exercise mimetics: harnessing the therapeutic effects of physical activity. Nat. Rev. Drug Discov. 20, 862–879 (2021).

pubmed: 34103713 doi: 10.1038/s41573-021-00217-1

Darragh, I. A. J. & Egan, B. Considerations for exerkine research focusing on the response to exercise training. J. Sport Health Sci. 13, 130–132 (2024).

pubmed: 37926387 doi: 10.1016/j.jshs.2023.11.002

Reghupaty, S. C., Dall, N. R. & Svensson, K. J. Hallmarks of the metabolic secretome. Trends Endocrinol. Metab. 35, 49–61 (2024).

pubmed: 37845120 doi: 10.1016/j.tem.2023.09.006

Baker, S. A. & Rutter, J. Metabolites as signalling molecules. Nat. Rev. Mol. Cell Biol. 24, 355–374 (2023).

pubmed: 36635456 doi: 10.1038/s41580-022-00572-w

Lone, J. B., Long, J. Z. & Svensson, K. J. Size matters: the biochemical logic of ligand type in endocrine crosstalk. Life Metab. 3, load048 (2024).

pubmed: 38425548 doi: 10.1093/lifemeta/load048

Boström, P. et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481, 463–468 (2012).

pubmed: 22237023 pmcid: 3522098 doi: 10.1038/nature10777

Xu, X. et al. Follistatin-like 1 as a novel adipomyokine related to insulin resistance and physical activity. J. Clin. Endocrinol. Metab. 105, e4499–e4509 (2020).

doi: 10.1210/clinem/dgaa629

Nam, J. S. et al. Follistatin‐like 1 is a myokine regulating lipid mobilization during endurance exercise and recovery. Obesity 32, 352–362 (2024).

pubmed: 38018497 doi: 10.1002/oby.23949

Kon, M., Ebi, Y. & Nakagaki, K. Effects of acute sprint interval exercise on follistatin-like 1 and apelin secretions. Arch. Physiol. Biochem. 127, 223–227 (2021).

pubmed: 31232102 doi: 10.1080/13813455.2019.1628067

Nam, H.-J., Kim, I., Bowie, J. U. & Kim, S. Metazoans evolved by taking domains from soluble proteins to expand intercellular communication network. Sci. Rep. 5, 9576 (2015).

pubmed: 25923201 pmcid: 4894438 doi: 10.1038/srep09576

Contrepois, K. et al. Molecular choreography of acute exercise. Cell 181, 1112–1130.e16 (2020).

pubmed: 32470399 pmcid: 7299174 doi: 10.1016/j.cell.2020.04.043

Mi, M. Y. et al. Plasma proteomic kinetics in response to acute exercise. Mol. Cell. Proteom. 22, 100601 (2023).

doi: 10.1016/j.mcpro.2023.100601

Parker, B. L. et al. Multiplexed temporal quantification of the exercise-regulated plasma peptidome. Mol. Cell. Proteom. 16, 2055–2068 (2017).

doi: 10.1074/mcp.RA117.000020

Robbins, J. M. et al. Human plasma proteomic profiles indicative of cardiorespiratory fitness. Nat. Metab. 3, 786–797 (2021).

pubmed: 34045743 pmcid: 9216203 doi: 10.1038/s42255-021-00400-z

Robbins, J. M. et al. Plasma proteomic changes in response to exercise training are associated with cardiorespiratory fitness adaptations. JCI Insight 8, e165867 (2023).

pubmed: 37036009 pmcid: 10132160 doi: 10.1172/jci.insight.165867

Wei, W. et al. Organism-wide, cell-type-specific secretome mapping of exercise training in mice. Cell Metab. 35, 1261–1279.e11 (2023).

pubmed: 37141889 doi: 10.1016/j.cmet.2023.04.011

Brooks, G. A. The science and translation of Lactate shuttle theory. Cell Metab. 27, 757–785 (2018).

pubmed: 29617642 doi: 10.1016/j.cmet.2018.03.008

Hui, S. et al. Glucose feeds the TCA cycle via circulating lactate. Nature 551, 115–118 (2017).

pubmed: 29045397 pmcid: 5898814 doi: 10.1038/nature24057

Rabinowitz, J. D. & Enerbäck, S. Lactate: the ugly duckling of energy metabolism. Nat. Metab. 2, 566–571 (2020).

pubmed: 32694798 pmcid: 7983055 doi: 10.1038/s42255-020-0243-4

Brooks, G. A. Lactate as a fulcrum of metabolism. Redox Biol. 35, 101454 (2020).

pubmed: 32113910 pmcid: 7284908 doi: 10.1016/j.redox.2020.101454

Brooks, G. A. et al. Lactate as a major myokine and exerkine. Nat. Rev. Endocrinol. 18, 712–712 (2022).

pubmed: 35915256 doi: 10.1038/s41574-022-00724-0

Howarth, K. R., LeBlanc, P. J., Heigenhauser, G. J. F. & Gibala, M. J. Effect of endurance training on muscle TCA cycle metabolism during exercise in humans. J. Appl. Physiol. 97, 579–584 (2004).

pubmed: 15121741 doi: 10.1152/japplphysiol.01344.2003

Schranner, D., Kastenmüller, G., Schönfelder, M., Römisch-Margl, W. & Wackerhage, H. Metabolite concentration changes in humans after a bout of exercise: a systematic review of exercise metabolomics studies. Sports Med. - Open 6, 11 (2020).

pubmed: 32040782 pmcid: 7010904 doi: 10.1186/s40798-020-0238-4

Ferreira, L. M. R. et al. Intermediary metabolism: an intricate network at the crossroads of cell fate and function. Biochim. Biophys. Acta BBA - Mol. Basis Dis. 1866, 165887 (2020).

doi: 10.1016/j.bbadis.2020.165887

Veerappa, S. & McClure, J. Intermediary metabolism. Anaesth. Intensive Care Med. 21, 162–167 (2020).

doi: 10.1016/j.mpaic.2020.01.003

Lewis, G. D. et al. Metabolic signatures of exercise in human plasma. Sci. Transl. Med. 2, 33a37 (2010).

Abdelmoez, A. M. et al. Cell selectivity in succinate receptor SUCNR1 /GPR91 signaling in skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 324, E289–E298 (2023).

pubmed: 36812387 doi: 10.1152/ajpendo.00009.2023

Reddy, A. et al. pH-Gated succinate secretion regulates muscle remodeling in response to exercise. Cell 183, 62–75.e17 (2020).

pubmed: 32946811 pmcid: 7778787 doi: 10.1016/j.cell.2020.08.039

Wang, T. et al. Succinate induces skeletal muscle fiber remodeling via SUCNR1 signaling. EMBO Rep. 20, e47892 (2019).

pubmed: 31318145 pmcid: 6727026 doi: 10.15252/embr.201947892

Murphy, M. P. & O’Neill, L. A. J. Krebs cycle reimagined: the emerging roles of succinate and itaconate as signal transducers. Cell 174, 780–784 (2018).

pubmed: 30096309 doi: 10.1016/j.cell.2018.07.030

Reddy, A. et al. Monocarboxylate transporters facilitate succinate uptake into brown adipocytes. Nat. Metab. 6, 567–577 (2024).

pubmed: 38378996 doi: 10.1038/s42255-024-00981-5

Stanford, K. I. et al. 12,13-diHOME: an exercise-induced lipokine that increases skeletal muscle fatty acid uptake. Cell Metab. 27, 1111–1120.e3 (2018).

pubmed: 29719226 pmcid: 5935136 doi: 10.1016/j.cmet.2018.03.020

Kitase, Y. et al. β-aminoisobutyric acid, l-BAIBA, is a muscle-derived osteocyte survival factor. Cell Rep. 22, 1531–1544 (2018).

pubmed: 29425508 pmcid: 5832359 doi: 10.1016/j.celrep.2018.01.041

Roberts, L. D. et al. β-aminoisobutyric acid induces browning of white fat and hepatic β-oxidation and is inversely correlated with cardiometabolic risk factors. Cell Metab. 19, 96–108 (2014).

pubmed: 24411942 pmcid: 4017355 doi: 10.1016/j.cmet.2013.12.003

Morville, T., Sahl, R. E., Moritz, T., Helge, J. W. & Clemmensen, C. Plasma metabolome profiling of resistance exercise and endurance exercise in humans. Cell Rep. 33, 108554 (2020).

pubmed: 33378671 doi: 10.1016/j.celrep.2020.108554

Nemeth, K., Bayraktar, R., Ferracin, M. & Calin, G. A. Non-coding RNAs in disease: from mechanisms to therapeutics. Nat. Rev. Genet. 25, 211–232 (2024).

pubmed: 37968332 doi: 10.1038/s41576-023-00662-1

Statello, L., Guo, C.-J., Chen, L.-L. & Huarte, M. Gene regulation by long non-coding RNAs and its biological functions. Nat. Rev. Mol. Cell Biol. 22, 96–118 (2021).

pubmed: 33353982 doi: 10.1038/s41580-020-00315-9

De Goede, O. M. et al. Population-scale tissue transcriptomics maps long non-coding RNAs to complex disease. Cell 184, 2633–2648.e19 (2021).

pubmed: 33864768 pmcid: 8651477 doi: 10.1016/j.cell.2021.03.050

Guo, Z. et al. Genome-wide survey of tissue-specific microRNA and transcription factor regulatory networks in 12 tissues. Sci. Rep. 4, 5150 (2014).

pubmed: 24889152 pmcid: 5381490 doi: 10.1038/srep05150

Just, J. et al. Blood flow-restricted resistance exercise alters the surface profile, miRNA cargo and functional impact of circulating extracellular vesicles. Sci. Rep. 10, 5835 (2020).

pubmed: 32245988 pmcid: 7125173 doi: 10.1038/s41598-020-62456-3

Ma, C. et al. Moderate exercise enhances endothelial progenitor cell exosomes release and function. Med. Sci. Sports Exerc. 50, 2024–2032 (2018).

pubmed: 30222687 doi: 10.1249/MSS.0000000000001672

Warnier, G. et al. Effects of a 6-wk sprint interval training protocol at different altitudes on circulating extracellular vesicles. Med. Sci. Sports Exerc. 55, 46–54 (2023).

pubmed: 36069865 doi: 10.1249/MSS.0000000000003031

Bye, A. et al. Circulating microRNAs and aerobic fitness – the HUNT study. PLoS ONE 8, e57496 (2013).

pubmed: 23469005 pmcid: 3585333 doi: 10.1371/journal.pone.0057496

Rutkovskiy, A. et al. Circulating microRNA-210 concentrations in patients with acute heart failure: data from the Akershus cardiac examination 2 study. Clin. Chem. 67, 889–898 (2021).

pubmed: 33783502 doi: 10.1093/clinchem/hvab030

Røsjø, H. et al. Prognostic value of circulating MicroRNA-210 levels in patients with moderate to severe aortic stenosis. PLoS One 9, e91812 (2014).

pubmed: 24626394 pmcid: 3953554 doi: 10.1371/journal.pone.0091812

Bye, A. et al. Circulating microRNAs predict future fatal myocardial infarction in healthy individuals—the HUNT study. J. Mol. Cell. Cardiol. 97, 162–168 (2016).

pubmed: 27192016 doi: 10.1016/j.yjmcc.2016.05.009

Stølen, T. O. et al. Exercise training reveals micro-RNAs associated with improved cardiac function and electrophysiology in rats with heart failure after myocardial infarction. J. Mol. Cell. Cardiol. 148, 106–119 (2020).

pubmed: 32918915 doi: 10.1016/j.yjmcc.2020.08.015

Bei, Y. et al. Exercise-induced miR-210 promotes cardiomyocyte proliferation and survival and mediates exercise-induced cardiac protection against ischemia/reperfusion injury. Research 7, 0327 (2024).

pubmed: 38410280 pmcid: 10895486 doi: 10.34133/research.0327

Kotewitsch, M., Heimer, M., Schmitz, B. & Mooren, F. C. Non-coding RNAs in exercise immunology: a systematic review. J. Sport Health Sci. https://doi.org/10.1016/j.jshs.2023.11.001 (2023).

Zhang, T. et al. miR-143 regulates memory T cell differentiation by reprogramming T cell metabolism. J. Immunol. 201, 2165–2175 (2018).

pubmed: 30150287 doi: 10.4049/jimmunol.1800230

Ye, Z. et al. Regulation of miR-181a expression in T cell aging. Nat. Commun. 9, 3060 (2018).

pubmed: 30076309 pmcid: 6076328 doi: 10.1038/s41467-018-05552-3

Miranda, K. et al. MicroRNA-30 modulates metabolic inflammation by regulating Notch signaling in adipose tissue macrophages. Int. J. Obes. 42, 1140–1150 (2018).

doi: 10.1038/s41366-018-0114-1

Silva, G. J. J., Bye, A., El Azzouzi, H. & Wisløff, U. MicroRNAs as important regulators of exercise adaptation. Prog. Cardiovasc. Dis. 60, 130–151 (2017).

pubmed: 28666746 doi: 10.1016/j.pcad.2017.06.003

Russell, A. P. et al. Regulation of miRNAs in human skeletal muscle following acute endurance exercise and short‐term endurance training. J. Physiol. 591, 4637–4653 (2013).

pubmed: 23798494 pmcid: 3784204 doi: 10.1113/jphysiol.2013.255695

Safdar, A., Abadi, A., Akhtar, M., Hettinga, B. P. & Tarnopolsky, M. A. miRNA in the regulation of skeletal muscle adaptation to acute endurance exercise in C57Bl/6J male mice. PLOS One 4, e5610 (2009).

pubmed: 19440340 pmcid: 2680038 doi: 10.1371/journal.pone.0005610

Bonilauri, B. & Dallagiovanna, B. Long non-coding RNAs are differentially expressed after different exercise training programs. Front. Physiol. 11, 567614 (2020).

pubmed: 33071823 pmcid: 7533564 doi: 10.3389/fphys.2020.567614

Wohlwend, M. et al. The exercise-induced long noncoding RNA CYTOR promotes fast-twitch myogenesis in aging. Sci. Transl. Med. 13, eabc7367 (2021).

pubmed: 34878822 doi: 10.1126/scitranslmed.abc7367

Trewin, A. J. et al. Long non-coding RNA Tug1 modulates mitochondrial and myogenic responses to exercise in skeletal muscle. BMC Biol. 20, 164 (2022).

pubmed: 35850762 pmcid: 9295458 doi: 10.1186/s12915-022-01366-4

Chen, W., Ye, Q. & Dong, Y. Long term exercise-derived exosomal LncRNA CRNDE mitigates myocardial infarction injury through miR-489-3p/Nrf2 signaling axis. Nanomed. Nanotechnol. Biol. Med. 55, 102717 (2024).

doi: 10.1016/j.nano.2023.102717

Done, A. J. & Traustadóttir, T. Nrf2 mediates redox adaptations to exercise. Redox Biol. 10, 191–199 (2016).

pubmed: 27770706 pmcid: 5078682 doi: 10.1016/j.redox.2016.10.003

Gao, R. et al. Long noncoding RNA cardiac physiological hypertrophy-associated regulator induces cardiac physiological hypertrophy and promotes functional recovery after myocardial ischemia-reperfusion injury. Circulation 144, 303–317 (2021).

pubmed: 34015936 doi: 10.1161/CIRCULATIONAHA.120.050446

Li, H. et al. lncExACT1 and DCHS2 regulate physiological and pathological cardiac growth. Circulation 145, 1218–1233 (2022).

pubmed: 35114812 pmcid: 9056949 doi: 10.1161/CIRCULATIONAHA.121.056850

Zhu, Y. et al. Circ-Ddx60 contributes to the antihypertrophic memory of exercise hypertrophic preconditioning. J. Adv. Res. 46, 113–121 (2023).

pubmed: 35718079 doi: 10.1016/j.jare.2022.06.005

Wang, L. et al. Exercise-induced circular RNA circUtrn is required for cardiac physiological hypertrophy and prevents myocardial ischaemia–reperfusion injury. Cardiovasc. Res. 119, 2638–2652 (2023).

pubmed: 37897547 doi: 10.1093/cvr/cvad161

Cesana, M. et al. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell 147, 358–369 (2011).

pubmed: 22000014 pmcid: 3234495 doi: 10.1016/j.cell.2011.09.028

Sen, R., Ghosal, S., Das, S., Balti, S. & Chakrabarti, J. Competing endogenous RNA: the key to posttranscriptional regulation. Sci. World J. 2014, 896206 (2014).

doi: 10.1155/2014/896206

Nie, M., Liu, Q. & Yan, C. Construction of a novel lncRNA-miRNA-mRNA competing endogenous RNA network in muscle in response to exercise training. Gen. Physiol. Biophys. 42, 123–133 (2023).

pubmed: 36896942 doi: 10.4149/gpb_2022062

Wu, J. et al. LncRNA/miRNA/mRNA ceRNA network analysis in spinal cord injury rat with physical exercise therapy. PeerJ 10, e13783 (2022).

pubmed: 35923891 pmcid: 9341448 doi: 10.7717/peerj.13783

Wang, L. et al. METTL14 is required for exercise-induced cardiac hypertrophy and protects against myocardial ischemia-reperfusion injury. Nat. Commun. 13, 6762 (2022).

pubmed: 36351918 pmcid: 9646739 doi: 10.1038/s41467-022-34434-y

Yan, L. et al. Physical exercise prevented stress‐induced anxiety via improving brain RNA methylation. Adv. Sci. 9, 2105731 (2022).

doi: 10.1002/advs.202105731

Subbotina, E. et al. Musclin is an activity-stimulated myokine that enhances physical endurance. Proc. Natl Acad. Sci. 112, 16042–16047 (2015).

pubmed: 26668395 pmcid: 4702977 doi: 10.1073/pnas.1514250112

Shweiki, D., Itin, A., Soffer, D. & Keshet, E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 359, 843–845 (1992).

pubmed: 1279431 doi: 10.1038/359843a0

Ingerslev, B. et al. Angiopoietin-like protein 4 is an exercise-induced hepatokine in humans, regulated by glucagon and cAMP. Mol. Metab. 6, 1286–1295 (2017).

pubmed: 29031727 pmcid: 5641605 doi: 10.1016/j.molmet.2017.06.018

Hou, Z. et al. Longterm exercise-derived exosomal miR-342-5p: a novel exerkine for cardioprotection. Circ. Res. 124, 1386–1400 (2019).

pubmed: 30879399 doi: 10.1161/CIRCRESAHA.118.314635

Davis, B. D. & Tai, P.-C. The mechanism of protein secretion across membranes. Nature 283, 433–438 (1980).

pubmed: 7352023 doi: 10.1038/283433a0

Hegde, R. S. & Keenan, R. J. The mechanisms of integral membrane protein biogenesis. Nat. Rev. Mol. Cell Biol. 23, 107–124 (2022).

pubmed: 34556847 doi: 10.1038/s41580-021-00413-2

Hosoya, M. et al. Molecular and functional characteristics of APJ. J. Biol. Chem. 275, 21061–21067 (2000).

pubmed: 10777510 doi: 10.1074/jbc.M908417199

Kawamata, Y. et al. Molecular properties of apelin: tissue distribution and receptor binding. Biochim. Biophys. Acta BBA - Mol. Cell Res. 1538, 162–171 (2001).

doi: 10.1016/S0167-4889(00)00143-9

Kelly, R. B. Pathways of protein secretion in eukaryotes. Science 230, 25–32 (1985).

pubmed: 2994224 doi: 10.1126/science.2994224

Nickel, W. & Rabouille, C. Mechanisms of regulated unconventional protein secretion. Nat. Rev. Mol. Cell Biol. 10, 148–155 (2009).

pubmed: 19122676 doi: 10.1038/nrm2617

Rabouille, C. Pathways of unconventional protein secretion. Trends Cell Biol. 27, 230–240 (2017).

pubmed: 27989656 doi: 10.1016/j.tcb.2016.11.007

Sahlin, K., Katz, A. & Henriksson, J. Redox state and lactate accumulation in human skeletal muscle during dynamic exercise. Biochem. J. 245, 551–556 (1987).

pubmed: 3663177 pmcid: 1148157 doi: 10.1042/bj2450551

Spriet, L. L., Howlett, R. A. & Heigenhauser, G. J. F. An enzymatic approach to lactate production in human skeletal muscle during exercise. Med. Sci. Sports Exerc. 32, 756–763 (2000).

pubmed: 10776894 doi: 10.1097/00005768-200004000-00007

Gould, S. J. & Raposo, G. As we wait: coping with an imperfect nomenclature for extracellular vesicles. J. Extracell. Vesicles 2, 20389 (2013).

doi: 10.3402/jev.v2i0.20389

Xu, R. et al. Extracellular vesicles in cancer—implications for future improvements in cancer care. Nat. Rev. Clin. Oncol. 15, 617–638 (2018).

pubmed: 29795272 doi: 10.1038/s41571-018-0036-9

Hill, A. F. Extracellular vesicles and neurodegenerative diseases. J. Neurosci. 39, 9269–9273 (2019).

pubmed: 31748282 pmcid: 6867808 doi: 10.1523/JNEUROSCI.0147-18.2019

Buzas, E. I. The roles of extracellular vesicles in the immune system. Nat. Rev. Immunol. 23, 236–250 (2023).

pubmed: 35927511 doi: 10.1038/s41577-022-00763-8

Hendrix, A. et al. Extracellular vesicle analysis. Nat. Rev. Methods Prim. 3, 56 (2023).

doi: 10.1038/s43586-023-00240-z

Frühbeis, C., Helmig, S., Tug, S., Simon, P. & Krämer‐Albers, E. Physical exercise induces rapid release of small extracellular vesicles into the circulation. J. Extracell. Vesicles 4, 28239 (2015).

pubmed: 26142461 doi: 10.3402/jev.v4.28239

McIlvenna, L. C. et al. Single vesicle analysis reveals the release of tetraspanin positive extracellular vesicles into circulation with high intensity intermittent exercise. J. Physiol. 601, 5093–5106 (2023).

pubmed: 36855276 doi: 10.1113/JP284047

Delgado-Peraza, F. et al. Neuron-derived extracellular vesicles in blood reveal effects of exercise in Alzheimer’s disease. Alzheimers Res. Ther. 15, 156 (2023).

pubmed: 37730689 pmcid: 10510190 doi: 10.1186/s13195-023-01303-9

Ma, S. et al. Skeletal muscle-derived extracellular vesicles transport glycolytic enzymes to mediate muscle-to-bone crosstalk. Cell Metab. 35, 2028–2043.e7 (2023).

pubmed: 37939660 doi: 10.1016/j.cmet.2023.10.013

Peng, B. et al. Red blood cell extracellular vesicles deliver therapeutic siRNAs to skeletal muscles for treatment of cancer cachexia. Mol. Ther. 31, 1418–1436 (2023).

pubmed: 37016578 pmcid: 10188904 doi: 10.1016/j.ymthe.2023.03.036

Whitham, M. et al. Extracellular vesicles provide a means for tissue crosstalk during exercise. Cell Metab. 27, 237–251.e4 (2018).

pubmed: 29320704 doi: 10.1016/j.cmet.2017.12.001

Vechetti, I. J., Valentino, T., Mobley, C. B. & McCarthy, J. J. The role of extracellular vesicles in skeletal muscle and systematic adaptation to exercise. J. Physiol. 599, 845–861 (2021).

pubmed: 31944292 doi: 10.1113/JP278929

Bayraktar, R., Van Roosbroeck, K. & Calin, G. A. Cell‐to‐cell communication: microRNAs as hormones. Mol. Oncol. 11, 1673–1686 (2017).

pubmed: 29024380 pmcid: 5709614 doi: 10.1002/1878-0261.12144

Liu, T. et al. EVmiRNA: a database of miRNA profiling in extracellular vesicles. Nucleic Acids Res 47, D89–D93 (2019).

pubmed: 30335161 doi: 10.1093/nar/gky985

Mittelbrunn, M. & Sánchez-Madrid, F. Intercellular communication: diverse structures for exchange of genetic information. Nat. Rev. Mol. Cell Biol. 13, 328–335 (2012).

pubmed: 22510790 pmcid: 3738855 doi: 10.1038/nrm3335

Doncheva, A. I. et al. Extracellular vesicles and microRNAs are altered in response to exercise, insulin sensitivity and overweight. Acta Physiol. 236, e13862 (2022).

doi: 10.1111/apha.13862

Peng, H. et al. A mechanosensitive lipolytic factor in the bone marrow promotes osteogenesis and lymphopoiesis. Cell Metab. 34, 1168–1182.e6 (2022).

pubmed: 35705079 doi: 10.1016/j.cmet.2022.05.009

Islam, M. R. et al. Exercise hormone irisin is a critical regulator of cognitive function. Nat. Metab. 3, 1058–1070 (2021).

pubmed: 34417591 pmcid: 10317538 doi: 10.1038/s42255-021-00438-z

Lourenco, M. V. et al. Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models. Nat. Med. 25, 165–175 (2019).

pubmed: 30617325 pmcid: 6327967 doi: 10.1038/s41591-018-0275-4

Wrann, C. D. et al. Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell Metab. 18, 649–659 (2013).

pubmed: 24120943 pmcid: 3980968 doi: 10.1016/j.cmet.2013.09.008

Rao, R. R. et al. Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis. Cell 157, 1279–1291 (2014).

pubmed: 24906147 pmcid: 4131287 doi: 10.1016/j.cell.2014.03.065

Uhlén, M. et al. Tissue-based map of the human proteome. Science 347, 1260419 (2015).

pubmed: 25613900 doi: 10.1126/science.1260419

Aoi, W. et al. A novel myokine, secreted protein acidic and rich in cysteine (SPARC), suppresses colon tumorigenesis via regular exercise. Gut 62, 882–889 (2013).

pubmed: 22851666 doi: 10.1136/gutjnl-2011-300776

Jørgensen, L. H. et al. SPARC interacts with actin in skeletal muscle in vitro and in vivo. Am. J. Pathol. 187, 457–474 (2017).

pubmed: 27908613 doi: 10.1016/j.ajpath.2016.10.013

Gu, H. et al. Soluble klotho improves hepatic glucose and lipid homeostasis in type 2 diabetes. Mol. Ther. Methods Clin. Dev. 18, 811–823 (2020).

pubmed: 32953932 pmcid: 7479259 doi: 10.1016/j.omtm.2020.08.002

Rao, Z., Zheng, L., Huang, H., Feng, Y. & Shi, R. α-Klotho expression in mouse tissues following acute exhaustive exercise. Front. Physiol. 10, 1498 (2019).

pubmed: 31920703 pmcid: 6919267 doi: 10.3389/fphys.2019.01498

Seldin, M. M., Peterson, J. M., Byerly, M. S., Wei, Z. & Wong, G. W. Myonectin (CTRP15), a novel myokine that links skeletal muscle to systemic lipid homeostasis. J. Biol. Chem. 287, 11968–11980 (2012).

pubmed: 22351773 pmcid: 3320944 doi: 10.1074/jbc.M111.336834

De Nardo, W. et al. Proteomic analysis reveals exercise training induced remodelling of hepatokine secretion and uncovers syndecan-4 as a regulator of hepatic lipid metabolism. Mol. Metab. 60, 101491 (2022).

pubmed: 35381388 pmcid: 9034320 doi: 10.1016/j.molmet.2022.101491

Chong, M. C., Silva, A., James, P. F., Wu, S. S. X. & Howitt, J. Exercise increases the release of NAMPT in extracellular vesicles and alters NAD

Orange, S. T. et al. Acute aerobic exercise‐conditioned serum reduces colon cancer cell proliferation in vitro through interleukin‐6‐induced regulation of DNA damage. Int. J. Cancer 151, 265–274 (2022).

pubmed: 35213038 pmcid: 9314683 doi: 10.1002/ijc.33982

Kasper, A. M., Turner, D. C., Martin, N. R. W. & Sharples, A. P. Mimicking exercise in three-dimensional bioengineered skeletal muscle to investigate cellular and molecular mechanisms of physiological adaptation. J. Cell. Physiol. 233, 1985–1998 (2018).

pubmed: 28158895 doi: 10.1002/jcp.25840

Lautaoja, J. H. et al. Mimicking exercise in vitro: effects of myotube contractions and mechanical stretch on omics. Am. J. Physiol. -Cell Physiol. 324, C886–C892 (2023).

pubmed: 36881402 doi: 10.1152/ajpcell.00586.2022

Watanabe, L. P. & Riddle, N. C. New opportunities: Drosophila as a model system for exercise research. J. Appl. Physiol. 127, 482–490 (2019).

pubmed: 31268829 doi: 10.1152/japplphysiol.00394.2019

Laranjeiro, R., Harinath, G., Burke, D., Braeckman, B. P. & Driscoll, M. Single swim sessions in C. elegans induce key features of mammalian exercise. BMC Biol. 15, 30 (2017).

pubmed: 28395669 pmcid: 5385602 doi: 10.1186/s12915-017-0368-4

Laranjeiro, R. et al. Swim exercise in Caenorhabditis elegans extends neuromuscular and gut healthspan, enhances learning ability, and protects against neurodegeneration. Proc. Natl Acad. Sci. 116, 23829–23839 (2019).

pubmed: 31685639 pmcid: 6876156 doi: 10.1073/pnas.1909210116

Poole, D. C. et al. Guidelines for animal exercise and training protocols for cardiovascular studies. Am. J. Physiol. Heart Circ. Physiol. 318, H1100–H1138 (2020).

pubmed: 32196357 pmcid: 7254566 doi: 10.1152/ajpheart.00697.2019

Crane, J. D. et al. Exercise-stimulated interleukin-15 is controlled by AMPK and regulates skin metabolism and aging. Aging Cell 14, 625–634 (2015).

pubmed: 25902870 pmcid: 4531076 doi: 10.1111/acel.12341

Chaweewannakorn, C. et al. Exercise‐evoked intramuscular neutrophil‐endothelial interactions support muscle performance and GLUT4 translocation: a mouse gnawing model study. J. Physiol. 598, 101–122 (2020).

pubmed: 31721209 doi: 10.1113/JP278564

Correia, J. C. et al. Muscle-secreted neurturin couples myofiber oxidative metabolism and slow motor neuron identity. Cell Metab. 33, 2215–2230.e8 (2021).

pubmed: 34592133 doi: 10.1016/j.cmet.2021.09.003

Dray, C. et al. Apelin stimulates glucose utilization in normal and obese insulin-resistant mice. Cell Metab. 8, 437–445 (2008).

pubmed: 19046574 doi: 10.1016/j.cmet.2008.10.003

Iwabu, M. et al. Adiponectin and AdipoR1 regulate PGC-1α and mitochondria by Ca2+ and AMPK/SIRT1. Nature 464, 1313–1319 (2010).

pubmed: 20357764 doi: 10.1038/nature08991

Loro, E. et al. Effect of interleukin-15 receptor alpha ablation on the metabolic responses to moderate exercise simulated by in vivo isometric muscle contractions. Front. Physiol. 10, 1439 (2019).

pubmed: 31849697 pmcid: 6901992 doi: 10.3389/fphys.2019.01439

Nyasha, M. R. et al. Effects of CX3CR1 and CXCR2 antagonists on running-dependent intramuscular neutrophil recruitments and myokine upregulation. Am. J. Physiol. Endocrinol. Metab. 324, E375–E389 (2023).

pubmed: 36856190 doi: 10.1152/ajpendo.00196.2022

Takahashi, H. et al. TGF-β2 is an exercise-induced adipokine that regulates glucose and fatty acid metabolism. Nat. Metab. 1, 291–303 (2019).

pubmed: 31032475 pmcid: 6481955 doi: 10.1038/s42255-018-0030-7

Vinel, C. et al. The exerkine apelin reverses age-associated sarcopenia. Nat. Med. 24, 1360–1371 (2018).

pubmed: 30061698 doi: 10.1038/s41591-018-0131-6

Yamauchi, T. et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat. Med. 8, 1288–1295 (2002).

pubmed: 12368907 doi: 10.1038/nm788

Yamauchi, T. et al. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat. Med. 13, 332–339 (2007).

pubmed: 17268472 doi: 10.1038/nm1557

Liu, Y. et al. TLR9 and beclin 1 crosstalk regulates muscle AMPK activation in exercise. Nature 578, 605–609 (2020).

pubmed: 32051584 pmcid: 7047589 doi: 10.1038/s41586-020-1992-7

Bjørnholt, J. V. et al. Fasting blood glucose: an underestimated risk factor for cardiovascular death. Results from a 22-year follow-up of healthy nondiabetic men. Diabetes Care 22, 45–49 (1999).

pubmed: 10333902 doi: 10.2337/diacare.22.1.45

Rao Kondapally Seshasai, S. et al. The emerging risk factors collaboration. diabetes mellitus, fasting glucose, and risk of cause-specific death. N. Engl. J. Med. 364, 829–841 (2011).

Halbgebauer, D. et al. Latent TGFβ-binding proteins regulate UCP1 expression and function via TGFβ2. Mol. Metab. 53, 101336 (2021).

pubmed: 34481123 pmcid: 8456047 doi: 10.1016/j.molmet.2021.101336

Gumucio, J. P., Sugg, K. B. & Mendias, C. L. TGF-β superfamily signaling in muscle and tendon adaptation to resistance exercise. Exerc. Sport Sci. Rev. 43, 93–99 (2015).

pubmed: 25607281 pmcid: 4369187 doi: 10.1249/JES.0000000000000041

Budagian, V., Bulanova, E., Paus, R. & Bulfonepaus, S. IL-15/IL-15 receptor biology: a guided tour through an expanding universe. Cytokine Growth Factor Rev. 17, 259–280 (2006).

pubmed: 16815076 doi: 10.1016/j.cytogfr.2006.05.001

Quinn, L. S. Interleukin-15: a muscle-derived cytokine regulating fat-to-lean body composition. J. Anim. Sci. 86, E75–E83 (2008).

pubmed: 17709786 doi: 10.2527/jas.2007-0458

Tamura, Y. et al. Upregulation of circulating IL-15 by treadmill running in healthy individuals: Is IL-15 an endocrine mediator of the beneficial effects of endurance exercise? Endocr. J. 58, 211–215 (2011).

pubmed: 21307608 doi: 10.1507/endocrj.K10E-400

Quinn, L. S., Anderson, B. G., Strait-Bodey, L., Stroud, A. M. & Argilés, J. M. Oversecretion of interleukin-15 from skeletal muscle reduces adiposity. Am. J. Physiol. Endocrinol. Metab. 296, E191–E202 (2009).

pubmed: 19001550 doi: 10.1152/ajpendo.90506.2008

Nielsen, A. R. et al. Association between interleukin-15 and obesity: interleukin-15 as a potential regulator of fat mass. J. Clin. Endocrinol. Metab. 93, 4486–4493 (2008).

pubmed: 18697873 doi: 10.1210/jc.2007-2561

Matsukawa, N. et al. The natriuretic peptide clearance receptor locally modulates the physiological effects of the natriuretic peptide system. Proc. Natl Acad. Sci. 96, 7403–7408 (1999).

pubmed: 10377427 pmcid: 22098 doi: 10.1073/pnas.96.13.7403

Yuan, Y. et al. Succinate promotes skeletal muscle protein synthesis via Erk1/2 signaling pathway. Mol. Med. Rep. 16, 7361–7366 (2017).

pubmed: 28944867 pmcid: 5865866 doi: 10.3892/mmr.2017.7554

Gordan, R., Gwathmey, J. K. & Xie, L.-H. Autonomic and endocrine control of cardiovascular function. World J. Cardiol. 7, 204 (2015).

pubmed: 25914789 pmcid: 4404375 doi: 10.4330/wjc.v7.i4.204

Lavin, K. M. et al. State of knowledge on molecular adaptations to exercise in humans: historical perspectives and future directions. Compr. Physiol. 12, 3193–3279 (2022).

Lu, L., Wu, D., Li, L. & Chen, L. Apelin/APJ system: a bifunctional target for cardiac hypertrophy. Int. J. Cardiol. 230, 164–170 (2017).

pubmed: 27979574 doi: 10.1016/j.ijcard.2016.11.215

Bei, Y. et al. Lymphangiogenesis contributes to exercise-induced physiological cardiac growth. J. Sport Health Sci. 11, 466–478 (2022).

pubmed: 35218948 pmcid: 9338339 doi: 10.1016/j.jshs.2022.02.005

Lee, H. W. et al. Effects of exercise training and TrkB blockade on cardiac function and BDNF-TrkB signaling postmyocardial infarction in rats. Am. J. Physiol. Heart Circ. Physiol. 315, H1821–H1834 (2018).

pubmed: 30311496 doi: 10.1152/ajpheart.00245.2018

Lee, H. W., Ahmad, M., Wang, H.-W. & Leenen, F. H. H. Effects of exercise training on brain-derived neurotrophic factor in skeletal muscle and heart of rats post myocardial infarction: cardiac brain-derived neurotrophic factor post myocardial infarction. Exp. Physiol. 102, 314–328 (2017).

pubmed: 28070911 doi: 10.1113/EP086049

Slagsvold, K. H. et al. Remote ischemic preconditioning preserves mitochondrial function and activates pro-survival protein kinase Akt in the left ventricle during cardiac surgery: a randomized trial. Int. J. Cardiol. 177, 409–417 (2014).

pubmed: 25456576 doi: 10.1016/j.ijcard.2014.09.206

Przyklenk, K. & Whittaker, P. Remote ischemic preconditioning: current knowledge, unresolved questions, and future priorities. J. Cardiovasc. Pharmacol. Ther. 16, 255–259 (2011).

pubmed: 21821525 doi: 10.1177/1074248411409040

Reboll, M. R. et al. Meteorin-like promotes heart repair through endothelial KIT receptor tyrosine kinase. Science 376, 1343–1347 (2022).

pubmed: 35709278 pmcid: 9838878 doi: 10.1126/science.abn3027

Cai, M.-X. et al. Exercise training activates neuregulin 1/ErbB signaling and promotes cardiac repair in a rat myocardial infarction model. Life Sci. 149, 1–9 (2016).

pubmed: 26892146 doi: 10.1016/j.lfs.2016.02.055

Scheja, L. & Heeren, J. The endocrine function of adipose tissues in health and cardiometabolic disease. Nat. Rev. Endocrinol. 15, 507–524 (2019).

pubmed: 31296970 doi: 10.1038/s41574-019-0230-6

Bartelt, A. & Heeren, J. Adipose tissue browning and metabolic health. Nat. Rev. Endocrinol. 10, 24–36 (2014).

pubmed: 24146030 doi: 10.1038/nrendo.2013.204

Lavie, C. J., Milani, R. V. & Ventura, H. O. Obesity and cardiovascular disease. J. Am. Coll. Cardiol. 53, 1925–1932 (2009).

pubmed: 19460605 doi: 10.1016/j.jacc.2008.12.068

Jedrychowski, M. P. et al. Detection and quantitation of circulating human irisin by tandem mass spectrometry. Cell Metab. 22, 734–740 (2015).

pubmed: 26278051 pmcid: 4802359 doi: 10.1016/j.cmet.2015.08.001

Raschke, S. et al. Evidence against a beneficial effect of Irisin in humans. PLoS One 8, e73680 (2013).

pubmed: 24040023 pmcid: 3770677 doi: 10.1371/journal.pone.0073680

Timmons, J. A., Baar, K., Davidsen, P. K. & Atherton, P. J. Is irisin a human exercise gene? Nature 488, E9–E10 (2012).

pubmed: 22932392 doi: 10.1038/nature11364

Kim, H. et al. Irisin mediates effects on bone and fat via αV integrin receptors. Cell 175, 1756–1768.e17 (2018).

pubmed: 30550785 pmcid: 6298040 doi: 10.1016/j.cell.2018.10.025

Mu, A. et al. Irisin acts through its integrin receptor in a two-step process involving extracellular Hsp90α. Mol. Cell 83, 1903–1920.e12 (2023).

doi: 10.1016/j.molcel.2023.05.008

Agudelo, L. Z. et al. Kynurenic acid and Gpr35 regulate adipose tissue energy homeostasis and inflammation. Cell Metab. 27, 378–392.e5 (2018).

pubmed: 29414686 doi: 10.1016/j.cmet.2018.01.004

Baht, G. S. et al. Meteorin-like facilitates skeletal muscle repair through a Stat3/IGF-1 mechanism. Nat. Metab. 2, 278–289 (2020).

pubmed: 32694780 pmcid: 7504545 doi: 10.1038/s42255-020-0184-y

Jung, T. W. et al. METRNL attenuates lipid-induced inflammation and insulin resistance via AMPK or PPARδ-dependent pathways in skeletal muscle of mice. Exp. Mol. Med. 50, 1–11 (2018).

pubmed: 30213948

Lee, D. E. et al. Meteorin-like is an injectable peptide that can enhance regeneration in aged muscle through immune-driven fibro/adipogenic progenitor signaling. Nat. Commun. 13, 7613 (2022).

pubmed: 36494364 pmcid: 9734561 doi: 10.1038/s41467-022-35390-3

Knudsen, J. G. et al. Role of IL-6 in exercise training- and cold-induced UCP1 expression in subcutaneous white adipose tissue. PLoS ONE 9, e84910 (2014).

pubmed: 24416310 pmcid: 3885654 doi: 10.1371/journal.pone.0084910

Kim, K. H. et al. Acute exercise induces FGF21 expression in mice and in healthy humans. PLoS One 8, e63517 (2013).

pubmed: 23667629 pmcid: 3646740 doi: 10.1371/journal.pone.0063517

Fisher, F. M. & Maratos-Flier, E. Understanding the physiology of FGF21. Annu. Rev. Physiol. 78, 223–241 (2016).

pubmed: 26654352 doi: 10.1146/annurev-physiol-021115-105339

Geng, L. et al. Exercise alleviates obesity-induced metabolic dysfunction via enhancing FGF21 sensitivity in adipose tissues. Cell Rep. 26, 2738–2752.e4 (2019).

pubmed: 30840894 doi: 10.1016/j.celrep.2019.02.014

Chilibeck, P. D., Sale, D. G. & Webber, C. E. Exercise and bone mineral density. Sports Med 19, 103–122 (1995).

pubmed: 7747001 doi: 10.2165/00007256-199519020-00003

Audzeyenka, I. et al. β-Aminoisobutyric acid (L-BAIBA) is a novel regulator of mitochondrial biogenesis and respiratory function in human podocytes. Sci. Rep. 13, 766 (2023).

pubmed: 36641502 pmcid: 9840613 doi: 10.1038/s41598-023-27914-8

Colaianni, G. et al. The myokine irisin increases cortical bone mass. Proc. Natl Acad. Sci. 112, 12157–12162 (2015).

pubmed: 26374841 pmcid: 4593131 doi: 10.1073/pnas.1516622112

Blazek, A. D. et al. Exercise-driven metabolic pathways in healthy cartilage. Osteoarthr. Cartil. 24, 1210–1222 (2016).

doi: 10.1016/j.joca.2016.02.004

Wu, D. et al. The blood–brain barrier: structure, regulation, and drug delivery. Signal Transduct. Target. Ther. 8, 217 (2023).

pubmed: 37231000 pmcid: 10212980 doi: 10.1038/s41392-023-01481-w

Gómez-Pinilla, F., Ying, Z., Roy, R. R., Molteni, R. & Edgerton, V. R. Voluntary exercise induces a BDNF-mediated mechanism that promotes neuroplasticity. J. Neurophysiol. 88, 2187–2195 (2002).

pubmed: 12424260 doi: 10.1152/jn.00152.2002

Kam, T.-I. et al. Amelioration of pathologic α-synuclein-induced Parkinson’s disease by irisin. Proc. Natl Acad. Sci. 119, e2204835119 (2022).

pubmed: 36044549 pmcid: 9457183 doi: 10.1073/pnas.2204835119

Lambertus, M. et al. L-lactate induces neurogenesis in the mouse ventricular-subventricular zone via the lactate receptor HCA1. Acta Physiol. 231, e13587 (2021).

doi: 10.1111/apha.13587

Morland, C. et al. Exercise induces cerebral VEGF and angiogenesis via the lactate receptor HCAR1. Nat. Commun. 8, 15557 (2017).

pubmed: 28534495 pmcid: 5457513 doi: 10.1038/ncomms15557

Zhang, P. et al. Early exercise improves cerebral blood flow through increased angiogenesis in experimental stroke rat model. J. Neuroeng. Rehabil. 10, 43 (2013).

pubmed: 23622352 pmcid: 3648391 doi: 10.1186/1743-0003-10-43

Yang, L. et al. GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand. Nat. Med. 23, 1158–1166 (2017).

pubmed: 28846099 doi: 10.1038/nm.4394

Moon, H. Y. et al. Running-induced systemic cathepsin B secretion is associated with memory function. Cell Metab. 24, 332–340 (2016).

pubmed: 27345423 pmcid: 6029441 doi: 10.1016/j.cmet.2016.05.025

Park, C. et al. Platelet factors are induced by longevity factor klotho and enhance cognition in young and aging mice. Nat. Aging 3, 1067–1078 (2023).

pubmed: 37587231 pmcid: 10501899 doi: 10.1038/s43587-023-00468-0

Schroer, A. B. et al. Platelet factors attenuate inflammation and rescue cognition in ageing. Nature 620, 1071–1079 (2023).

pubmed: 37587343 pmcid: 10468395 doi: 10.1038/s41586-023-06436-3

Leiter, O. et al. Platelet-derived exerkine CXCL4/platelet factor 4 rejuvenates hippocampal neurogenesis and restores cognitive function in aged mice. Nat. Commun. 14, 4375 (2023).

pubmed: 37587147 pmcid: 10432533 doi: 10.1038/s41467-023-39873-9

Leiter, O. et al. Exercise-induced activated platelets increase adult hippocampal precursor proliferation and promote neuronal differentiation. Stem Cell Rep. 12, 667–679 (2019).

doi: 10.1016/j.stemcr.2019.02.009

De Miguel, Z. et al. Exercise plasma boosts memory and dampens brain inflammation via clusterin. Nature 600, 494–499 (2021).

pubmed: 34880498 pmcid: 9721468 doi: 10.1038/s41586-021-04183-x

Horowitz, A. M. et al. Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain. Science 369, 167–173 (2020).

pubmed: 32646997 pmcid: 7879650 doi: 10.1126/science.aaw2622

Binder, D. K. & Scharfman, H. E. Brain-derived neurotrophic factor. Growth Factors 22, 123–131 (2004).

pubmed: 15518235 pmcid: 2504526 doi: 10.1080/08977190410001723308

Pedersen, B. K. Physical activity and muscle–brain crosstalk. Nat. Rev. Endocrinol. 15, 383–392 (2019).

pubmed: 30837717 doi: 10.1038/s41574-019-0174-x

Brindle, N. P. J., Saharinen, P. & Alitalo, K. Signaling and Functions of Angiopoietin-1 in Vascular Protection. Circ. Res. 98, 1014–1023 (2006).

pubmed: 16645151 pmcid: 2270395 doi: 10.1161/01.RES.0000218275.54089.12

McClung, J. M. et al. Muscle cell derived angiopoietin-1 contributes to both myogenesis and angiogenesis in the ischemic environment. Front. Physiol. 6, 161 (2015).

Lauritzen, K. H. et al. Lactate receptor sites link neurotransmission, neurovascular coupling, and brain energy metabolism. Cereb. Cortex 24, 2784–2795 (2014).

pubmed: 23696276 doi: 10.1093/cercor/bht136

Maugeri, G. et al. The role of exercise on peripheral nerve regeneration: from animal model to clinical application. Heliyon 7, e08281 (2021).

pubmed: 34765794 pmcid: 8571504 doi: 10.1016/j.heliyon.2021.e08281

Udina, E., Puigdemasa, A. & Navarro, X. Passive and active exercise improve regeneration and muscle reinnervation after peripheral nerve injury in the rat. Muscle Nerve 43, 500–509 (2011).

pubmed: 21305568 doi: 10.1002/mus.21912

Houle, J. D. & Côté, M. Axon regeneration and exercise‐dependent plasticity after spinal cord injury. Ann. N. Y. Acad. Sci. 1279, 154–163 (2013).

pubmed: 23531013 pmcid: 3616327 doi: 10.1111/nyas.12052

Park, J.-S. & Höke, A. Treadmill exercise induced functional recovery after peripheral nerve repair is associated with increased levels of neurotrophic factors. PLoS One 9, e90245 (2014).

pubmed: 24618564 pmcid: 3949693 doi: 10.1371/journal.pone.0090245

Preuss, C. V. & Anjum, F. Tocilizumab. [Updated 2022 Sep 21]. StatPearls [Internet] (2023).

Kistner, T. M., Pedersen, B. K. & Lieberman, D. E. Interleukin 6 as an energy allocator in muscle tissue. Nat. Metab. 4, 170–179 (2022).

pubmed: 35210610 doi: 10.1038/s42255-022-00538-4

Wedell-Neergaard, A.-S. et al. Exercise-induced changes in visceral adipose tissue mass are regulated by IL-6 signaling: a randomized controlled trial. Cell Metab. 29, 844–855.e3 (2019).

pubmed: 30595477 doi: 10.1016/j.cmet.2018.12.007

Trinh, B. et al. Blocking endogenous IL-6 impairs mobilization of free fatty acids during rest and exercise in lean and obese men. Cell Rep. Med. 2, 100396 (2021).

pubmed: 34622233 pmcid: 8484687 doi: 10.1016/j.xcrm.2021.100396

Bay, M. L. et al. Human immune cell mobilization during exercise: effect of IL‐6 receptor blockade. Exp. Physiol. 105, 2086–2098 (2020).

pubmed: 33006190 doi: 10.1113/EP088864

Christensen, R. H. et al. Aerobic exercise induces cardiac fat loss and alters cardiac muscle mass through an interleukin-6 receptor–dependent mechanism: cardiac analysis of a double-blind randomized controlled clinical trial in abdominally obese humans. Circulation 140, 1684–1686 (2019).

pubmed: 31710522 doi: 10.1161/CIRCULATIONAHA.119.042287

Trinh, B. et al. Amino acid metabolism and protein turnover in lean and obese humans during exercise—effect of IL-6 receptor blockade. J. Clin. Endocrinol. Metab. 107, 1854–1864 (2022).

pubmed: 35442403 doi: 10.1210/clinem/dgac239

Pedersen, L. et al. Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution. Cell Metab. 23, 554–562 (2016).

pubmed: 26895752 doi: 10.1016/j.cmet.2016.01.011

Djurhuus, S. S. et al. Exercise training to increase tumour natural killer‐cell infiltration in men with localised prostate cancer: a randomised controlled trial. BJU Int 131, 116–124 (2023).

pubmed: 35753072 doi: 10.1111/bju.15842

Schenk, A. et al. Distinct distribution patterns of exercise-induced natural killer cell mobilization into the circulation and tumor tissue of patients with prostate cancer. Am. J. Physiol. Cell Physiol. 323, C879–C884 (2022).

pubmed: 35912994 doi: 10.1152/ajpcell.00243.2022

Frydelund-Larsen, L. et al. Exercise induces interleukin-8 receptor (CXCR2) expression in human skeletal muscle: regulation of CXCR2 by exercise. Exp. Physiol. 92, 233–240 (2007).

pubmed: 17030560 doi: 10.1113/expphysiol.2006.034769

Stadtmann, A. & Zarbock, A. CXCR2: from bench to bedside. Front. Immunol. 3, 263 (2012).

Jurcevic, S. et al. The effect of a selective CXCR2 antagonist (AZD5069) on human blood neutrophil count and innate immune functions: effects of CXCR2 antagonism on human neutrophils. Br. J. Clin. Pharmacol. 80, 1324–1336 (2015).

pubmed: 26182832 pmcid: 4693488 doi: 10.1111/bcp.12724

Hoffman-Goetz, L. & Pedersen, B. K. Exercise and the immune system: a model of the stress response? Immunol. Today 15, 382–387 (1994).

pubmed: 7916952 doi: 10.1016/0167-5699(94)90177-5

Pedersen, B. K. Effects of exercise on lymphocytes and cytokines. Br. J. Sports Med. 34, 246–251 (2000).

pubmed: 10953894 pmcid: 1724218 doi: 10.1136/bjsm.34.4.246

Schlagheck, M. L. et al. Cellular immune response to acute exercise: comparison of endurance and resistance exercise. Eur. J. Haematol. 105, 75–84 (2020).

pubmed: 32221992 doi: 10.1111/ejh.13412

Peake, J. M., Neubauer, O., Walsh, N. P. & Simpson, R. J. Recovery of the immune system after exercise. J. Appl. Physiol. 122, 1077–1087 (2017).

pubmed: 27909225 doi: 10.1152/japplphysiol.00622.2016

Leonard, J. et al. The γc Family of Cytokines: Basic Biology to Therapeutic Ramifications. Immunity. 50, 832–850 (2019).

Straat, M. E. et al. Stimulation of the beta-2-adrenergic receptor with salbutamol activates human brown adipose tissue. Cell Rep. Med. 4, 100942 (2023).

pubmed: 36812890 pmcid: 9975328 doi: 10.1016/j.xcrm.2023.100942

Hansen, J. S. et al. Circulating follistatin is liver-derived and regulated by the glucagon-to-insulin ratio. J. Clin. Endocrinol. Metab. 101, 550–560 (2016).

pubmed: 26652766 doi: 10.1210/jc.2015-3668

Lee, S.-J. et al. Regulation of muscle mass by follistatin and activins. Mol. Endocrinol. 24, 1998–2008 (2010).

pubmed: 20810712 pmcid: 2954636 doi: 10.1210/me.2010-0127

Han, X. et al. Mechanisms involved in follistatin‐induced hypertrophy and increased insulin action in skeletal muscle. J. Cachexia Sarcopenia Muscle 10, 1241–1257 (2019).

pubmed: 31402604 pmcid: 7663972 doi: 10.1002/jcsm.12474

Winbanks, C. E. et al. Follistatin-mediated skeletal muscle hypertrophy is regulated by Smad3 and mTOR independently of myostatin. J. Cell Biol. 197, 997–1008 (2012).

pubmed: 22711699 pmcid: 3384410 doi: 10.1083/jcb.201109091

Catoire, M. et al. Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise. Proc. Natl. Acad. Sci. 111, E1043–52 (2014).

Norheim, F. et al. Regulation of angiopoietin-like protein 4 production during and after exercise. Physiol. Rep. 2, e12109 (2014).

pubmed: 25138789 pmcid: 4246580 doi: 10.14814/phy2.12109

Gray, N. E. et al. Angiopoietin-like 4 (Angptl4) protein is a physiological mediator of intracellular lipolysis in murine adipocytes. J. Biol. Chem. 287, 8444–8456 (2012).

pubmed: 22267746 pmcid: 3318686 doi: 10.1074/jbc.M111.294124

Zhang, H. et al. Aerobic exercise improves endothelial function and serum adropin levels in obese adolescents independent of body weight loss. Sci. Rep. 7, 17717 (2017).

pubmed: 29255252 pmcid: 5735148 doi: 10.1038/s41598-017-18086-3

Fujie, S. et al. Aerobic exercise restores aging‐associated reductions in arterial adropin levels and improves adropin‐induced nitric oxide‐dependent vasorelaxation. J. Am. Heart Assoc. 10, e020641 (2021).

pubmed: 33938228 pmcid: 8200711 doi: 10.1161/JAHA.120.020641

Parlak, H. et al. Adropin increases with swimming exercise and exerts a protective effect on the brain of aged rats. Exp. Gerontol. 169, 111972 (2022).

pubmed: 36216130 doi: 10.1016/j.exger.2022.111972

Yang, W. et al. Exercise suppresses NLRP3 inflammasome activation in mice with diet-induced NASH: a plausible role of adropin. Lab. Investig. 101, 369–380 (2021).

pubmed: 33268842 doi: 10.1038/s41374-020-00508-y

Kuramoto, K., Liang, H., Hong, J.-H. & He, C. Exercise-activated hepatic autophagy via the FN1-α5β1 integrin pathway drives metabolic benefits of exercise. Cell Metab. 35, 620–632.e5 (2023).

pubmed: 36812915 pmcid: 10079584 doi: 10.1016/j.cmet.2023.01.011

Chen, Y. et al. An acute bout of exercise suppresses appetite via central lactate metabolism. Neuroscience 510, 49–59 (2023).

pubmed: 36529295 doi: 10.1016/j.neuroscience.2022.11.013

Carrière, A. et al. Browning of white adipose cells by intermediate metabolites: an adaptive mechanism to alleviate redox pressure. Diabetes 63, 3253–3265 (2014).

pubmed: 24789919 doi: 10.2337/db13-1885

Henstridge, D. C., Febbraio, M. A. & Hargreaves, M. Heat shock proteins and exercise adaptations. Our knowledge thus far and the road still ahead. J. Appl. Physiol. 120, 683–691 (2016).

pubmed: 26679615 doi: 10.1152/japplphysiol.00811.2015

Xu, T. et al. HSF1 and NF-κB p65 participate in the process of exercise preconditioning attenuating pressure overload-induced pathological cardiac hypertrophy. Biochem. Biophys. Res. Commun. 460, 622–627 (2015).

pubmed: 25804640 doi: 10.1016/j.bbrc.2015.03.079

Archer, A. E., Von Schulze, A. T. & Geiger, P. C. Exercise, heat shock proteins and insulin resistance. Philos. Trans. R. Soc. B Biol. Sci. 373, 20160529 (2018).

doi: 10.1098/rstb.2016.0529

Noble, E. G., Milne, K. J. & Melling, C. W. J. Heat shock proteins and exercise: a primer. Appl. Physiol. Nutr. Metab. 33, 1050–1075 (2008).

pubmed: 18923583 doi: 10.1139/H08-069

Bei, Y. et al. Exercise-induced circulating extracellular vesicles protect against cardiac ischemia–reperfusion injury. Basic Res. Cardiol. 112, 38 (2017).

pubmed: 28534118 pmcid: 5748384 doi: 10.1007/s00395-017-0628-z

Thompson, H. S., Clarkson, P. M. & Scordilis, S. P. The repeated bout effect and heat shock proteins: intramuscular HSP27 and HSP70 expression following two bouts of eccentric exercise in humans. Acta Physiol. Scand. 174, 47–56 (2002).

pubmed: 11851596 doi: 10.1046/j.1365-201x.2002.00922.x

Goto, C. et al. Acute moderate-intensity exercise induces vasodilation through an increase in nitric oxide bioavailiability in humans. Am. J. Hypertens. 20, 825–830 (2007).

pubmed: 17679027 doi: 10.1016/j.amjhyper.2007.02.014

Jungersten, L., Ambring, A., Wall, B. & Wennmalm, Å. Both physical fitness and acute exercise regulate nitric oxide formation in healthy humans. J. Appl. Physiol. 82, 760–764 (1997).

pubmed: 9074960 doi: 10.1152/jappl.1997.82.3.760

Green, D. J., Maiorana, A., O’Driscoll, G. & Taylor, R. Effect of exercise training on endothelium‐derived nitric oxide function in humans. J. Physiol. 561, 1–25 (2004).

pubmed: 15375191 pmcid: 1665322 doi: 10.1113/jphysiol.2004.068197

Hambrecht, R. et al. Regular physical activity improves endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase. Circulation 107, 3152–3158 (2003).

pubmed: 12810615 doi: 10.1161/01.CIR.0000074229.93804.5C

Maiorana, A., O’Driscoll, G., Taylor, R. & Green, D. Exercise and the nitric oxide vasodilator system. Sports Med 33, 1013–1035 (2003).

pubmed: 14599231 doi: 10.2165/00007256-200333140-00001

Michel, T. & Feron, O. Nitric oxide synthases: which, where, how, and why? J. Clin. Investig. 100, 2146–2152 (1997).

pubmed: 9410890 pmcid: 508408 doi: 10.1172/JCI119750

Song, W., Kwak, H.-B., Kim, J.-H. & Lawler, J. M. Exercise training modulates the nitric oxide synthase profile in skeletal muscle from old rats. J. Gerontol. A. Biol. Sci. Med. Sci. 64A, 540–549 (2009).

pmcid: 2800810 doi: 10.1093/gerona/glp021

Powers, S. K., Duarte, J., Kavazis, A. N. & Talbert, E. E. Reactive oxygen species are signalling molecules for skeletal muscle adaptation. Exp. Physiol. 95, 1–9 (2010).

pubmed: 19880534 doi: 10.1113/expphysiol.2009.050526

He, F. et al. Redox mechanism of reactive oxygen species in exercise. Front. Physiol. 7, 486 (2016).

Niess, A. M. Response and adaptation of skeletal muscle to exercise—the role of reactive oxygen species. Front. Biosci. 12, 4826 (2007).

pubmed: 17569613 doi: 10.2741/2431

Leiter, O. et al. Selenium mediates exercise-induced adult neurogenesis and reverses learning deficits induced by hippocampal injury and aging. Cell Metab. 34, 408–423.e8 (2022).

pubmed: 35120590 doi: 10.1016/j.cmet.2022.01.005

Mulcahy, L. A., Pink, R. C. & Carter, D. R. F. Routes and mechanisms of extracellular vesicle uptake. J. Extracell. Vesicles 3, 24641 (2014).

doi: 10.3402/jev.v3.24641

Iannotta, D., Amruta, A., Kijas, A. W., Rowan, A. E. & Wolfram, J. Entry and exit of extracellular vesicles to and from the blood circulation. Nat. Nanotechnol. 19, 13–20 (2024).

pubmed: 38110531 doi: 10.1038/s41565-023-01522-z

World Health Organization. Global health estimates 2019: deaths by cause, age, sex, by country and by region, 2000–2019. https://www.who.int/data/gho/data/themes/mortality-and-global-health-estimates/ghe-leading-causes-of-death (2020).

Nocon, M. et al. Association of physical activity with all-cause and cardiovascular mortality: a systematic review and meta-analysis. Eur. J. Cardiovasc. Prev. Rehabil. 15, 239–246 (2008).

pubmed: 18525377 doi: 10.1097/HJR.0b013e3282f55e09

Schmid, D. & Leitzmann, M. F. Association between physical activity and mortality among breast cancer and colorectal cancer survivors: a systematic review and meta-analysis. Ann. Oncol. 25, 1293–1311 (2014).

pubmed: 24644304 doi: 10.1093/annonc/mdu012

Boniol, M., Dragomir, M., Autier, P. & Boyle, P. Physical activity and change in fasting glucose and HbA1c: a quantitative meta-analysis of randomized trials. Acta Diabetol. 54, 983–991 (2017).

pubmed: 28840356 doi: 10.1007/s00592-017-1037-3

Jadhav, R. A., Hazari, A., Monterio, A., Kumar, S. & Maiya, A. G. Effect of physical activity intervention in prediabetes: a systematic review with meta-analysis. J. Phys. Act. Health 14, 745–755 (2017).

pubmed: 28422560 doi: 10.1123/jpah.2016-0632

Stewart, R. A. H. et al. Physical activity and mortality in patients with stable coronary heart disease. J. Am. Coll. Cardiol. 70, 1689–1700 (2017).

pubmed: 28958324 doi: 10.1016/j.jacc.2017.08.017

Waschki, B. et al. Physical activity is the strongest predictor of all-cause mortality in patients With COPD. Chest 140, 331–342 (2011).

pubmed: 21273294 doi: 10.1378/chest.10-2521

Wen, C. et al. Pre‐stroke physical activity is associated with fewer post‐stroke complications, lower mortality and a better long‐term outcome. Eur. J. Neurol. 24, 1525–1531 (2017).

pubmed: 28926165 doi: 10.1111/ene.13463

Bull, F. C. et al. World Health Organization 2020 guidelines on physical activity and sedentary behaviour. Br. J. Sports Med. 54, 1451–1462 (2020).

pubmed: 33239350 doi: 10.1136/bjsports-2020-102955

Global action plan on physical activity 2018–2030: more active people for a healthier world. Geneva: World Health Organization; 2018. Licence: CC BY-NC-SA 3.0 IGO. https://www.who.int/publications/i/item/9789241514187 .

Fiuza-Luces, C., Garatachea, N., Berger, N. A. & Lucia, A. Exercise is the real polypill. Physiology 28, 330–358 (2013).

pubmed: 23997192 doi: 10.1152/physiol.00019.2013

Pareja-Galeano, H., Garatachea, N. & Lucia, A. Exercise as a polypill for chronic diseases. in Progress in Molecular Biology and Translational Science (ed. Bouchard, C.) vol. 135 497–526 (Academic Press, 2015).

Ho, M. et al. Impact of dietary and exercise interventions on weight change and metabolic outcomes in obese children and adolescents: a systematic review and meta-analysis of randomized trials. JAMA Pediatr. 167, 759 (2013).

pubmed: 23778747 doi: 10.1001/jamapediatrics.2013.1453

Miller, W., Koceja, D. & Hamilton, E. A meta-analysis of the past 25 years of weight loss research using diet, exercise or diet plus exercise intervention. Int. J. Obes. 21, 941–947 (1997).

doi: 10.1038/sj.ijo.0800499

Stoner, L. et al. Efficacy of exercise intervention for weight loss in overweight and obese adolescents: meta-analysis and implications. Sports Med 46, 1737–1751 (2016).

pubmed: 27139723 doi: 10.1007/s40279-016-0537-6

Huang, L., Fang, Y. & Tang, L. Comparisons of different exercise interventions on glycemic control and insulin resistance in prediabetes: a network meta-analysis. BMC Endocr. Disord. 21, 181 (2021).

pubmed: 34488728 pmcid: 8422751 doi: 10.1186/s12902-021-00846-y

Bonfante, I. L. P. et al. Combined training increases thermogenic fat activity in patients with overweight and type 2 diabetes. Int. J. Obes. 46, 1145–1154 (2022).

doi: 10.1038/s41366-022-01086-3

Martinez-Tellez, B. et al. No evidence of brown adipose tissue activation after 24 weeks of supervised exercise training in young sedentary adults in the ACTIBATE randomized controlled trial. Nat. Commun. 13, 5259 (2022).

pubmed: 36097264 pmcid: 9467993 doi: 10.1038/s41467-022-32502-x

Willis, L. H. et al. Effects of aerobic and/or resistance training on body mass and fat mass in overweight or obese adults. J. Appl. Physiol. 113, 1831–1837 (2012).

pubmed: 23019316 pmcid: 3544497 doi: 10.1152/japplphysiol.01370.2011

Chew, N. W. S. et al. The global burden of metabolic disease: data from 2000 to 2019. Cell Metab. 35, 414–428.e3 (2023).

pubmed: 36889281 doi: 10.1016/j.cmet.2023.02.003

Gourdy, P. et al. Apelin administration improves insulin sensitivity in overweight men during hyperinsulinaemic‐euglycaemic clamp. Diabetes Obes. Metab. 20, 157–164 (2018).

pubmed: 28681996 doi: 10.1111/dom.13055

Geng, L., Lam, K. S. L. & Xu, A. The therapeutic potential of FGF21 in metabolic diseases: from bench to clinic. Nat. Rev. Endocrinol. 16, 654–667 (2020).

pubmed: 32764725 doi: 10.1038/s41574-020-0386-0

Shao, W. & Jin, T. Hepatic hormone FGF21 and its analogues in clinical trials. Chronic Dis. Transl. Med. 8, 19–25 (2022).

pubmed: 35620160 pmcid: 9126297

Carey, A. L. et al. Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes 55, 2688–2697 (2006).

pubmed: 17003332 doi: 10.2337/db05-1404

Amaral, S. L., Papanek, P. E. & Greene, A. S. Angiotensin II and VEGF are involved in angiogenesis induced by short-term exercise training. Am. J. Physiol. Heart Circ. Physiol. 281, H1163–H1169 (2001).

pubmed: 11514283 doi: 10.1152/ajpheart.2001.281.3.H1163

Lu, X. et al. Effect and mechanism of intermittent myocardial ischemia induced by exercise on coronary collateral formation. Am. J. Phys. Med. Rehabil. 87, 803–814 (2008).

pubmed: 18688201 doi: 10.1097/PHM.0b013e31817faed0

Wu, G. et al. Exercise-induced expression of VEGF and salvation of myocardium in the early stage of myocardial infarction. Am. J. Physiol. Heart Circ. Physiol. 296, H389–H395 (2009).

pubmed: 19060119 doi: 10.1152/ajpheart.01393.2007

Moien-Afshari, F. et al. Exercise restores endothelial function independently of weight loss or hyperglycaemic status in db/db mice. Diabetologia 51, 1327–1337 (2008).

pubmed: 18437348 doi: 10.1007/s00125-008-0996-x

Nakamura, M. & Sadoshima, J. Mechanisms of physiological and pathological cardiac hypertrophy. Nat. Rev. Cardiol. 15, 387–407 (2018).

pubmed: 29674714 doi: 10.1038/s41569-018-0007-y

Cornelissen, V. A. & Smart, N. A. Exercise training for blood pressure: a systematic review and meta‐analysis. J. Am. Heart Assoc. 2, e004473 (2013).

pubmed: 23525435 pmcid: 3603230 doi: 10.1161/JAHA.112.004473

De Sousa, E. C. et al. Resistance training alone reduces systolic and diastolic blood pressure in prehypertensive and hypertensive individuals: meta-analysis. Hypertens. Res. 40, 927–931 (2017).

pubmed: 28769100 doi: 10.1038/hr.2017.69

Whelton, S. P., Chin, A., Xin, X. & He, J. Effect of aerobic exercise on blood pressure: a meta-analysis of randomized, controlled trials. Ann. Intern. Med. 136, 493 (2002).

pubmed: 11926784 doi: 10.7326/0003-4819-136-7-200204020-00006

Blumenthal, J. A. et al. Effects of the DASH diet alone and in combination with exercise and weight loss on blood pressure and cardiovascular biomarkers in men and women with high blood pressure. Arch. Intern. Med. 170, 126–135 (2010).

Ostman, C. et al. The effect of exercise training on clinical outcomes in patients with the metabolic syndrome: a systematic review and meta-analysis. Cardiovasc. Diabetol. 16, 110 (2017).

pubmed: 28854979 pmcid: 5577843 doi: 10.1186/s12933-017-0590-y

Jhamnani, S. et al. Meta-analysis of the effects of lifestyle modifications on coronary and carotid atherosclerotic burden. Am. J. Cardiol. 115, 268–275 (2015).

pubmed: 25465939 doi: 10.1016/j.amjcard.2014.10.035

Davignon, J. & Ganz, P. Role of endothelial dysfunction in atherosclerosis. Circulation 109, III27–32 (2004).

Ashor, A. W. et al. Exercise modalities and endothelial function: a systematic review and dose–response meta-analysis of randomized controlled trials. Sports Med. 45, 279–296 (2015).

pubmed: 25281334 doi: 10.1007/s40279-014-0272-9

Lawler, P. R., Filion, K. B. & Eisenberg, M. J. Efficacy of exercise-based cardiac rehabilitation post–myocardial infarction: a systematic review and meta-analysis of randomized controlled trials. Am. Heart J. 162, 571–584.e2 (2011).

pubmed: 21982647 doi: 10.1016/j.ahj.2011.07.017

ExTraMATCH Collaborative. Exercise training meta-analysis of trials in patients with chronic heart failure (ExTraMATCH). BMJ 328, 189–0 (2004).

pmcid: 318480 doi: 10.1136/bmj.37938.645220.EE

Taylor, R. et al. Exercise‐based rehabilitation for heart failure. Cochrane Database Syst. Rev. 2014, CD003331 (2014).

Cornelis, J., Beckers, P., Taeymans, J., Vrints, C. & Vissers, D. Comparing exercise training modalities in heart failure: a systematic review and meta-analysis. Int. J. Cardiol. 221, 867–876 (2016).

pubmed: 27434363 doi: 10.1016/j.ijcard.2016.07.105

Moreira, J. B. N. et al. Exercise reveals proline dehydrogenase as a potential target in heart failure. Prog. Cardiovasc. Dis. 62, 193–202 (2019).

pubmed: 30867130 doi: 10.1016/j.pcad.2019.03.002

Goto, C. et al. Effect of different intensities of exercise on endothelium-dependent vasodilation in humans: role of endothelium-dependent nitric oxide and oxidative stress. Circulation 108, 530–535 (2003).

pubmed: 12874192 doi: 10.1161/01.CIR.0000080893.55729.28

Higashi, Y. et al. Regular aerobic exercise augments endothelium-dependent vascular relaxation in normotensive as well as hypertensive subjects: role of endothelium-derived nitric oxide. Circulation 100, 1194–1202 (1999).

pubmed: 10484540 doi: 10.1161/01.CIR.100.11.1194

Brame, A. L. et al. Design, characterization, and first-in-human study of the vascular actions of a novel biased apelin receptor agonist. Hypertension 65, 834–840 (2015).

pubmed: 25712721 doi: 10.1161/HYPERTENSIONAHA.114.05099

Japp, A. G. et al. Acute cardiovascular effects of apelin in humans: potential role in patients with chronic heart failure. Circulation 121, 1818–1827 (2010).

pubmed: 20385929 doi: 10.1161/CIRCULATIONAHA.109.911339

Amadio, P. et al. Patho- physiological role of BDNF in fibrin clotting. Sci. Rep. 9, 389 (2019).

pubmed: 30674980 pmcid: 6344484 doi: 10.1038/s41598-018-37117-1

Yuan, R. et al. Vascular endothelial growth factor gene transfer therapy for coronary artery disease: a systematic review and meta‐analysis. Cardiovasc. Ther. 36, e12461 (2018).

pubmed: 30035366 doi: 10.1111/1755-5922.12461

Ferrara, N., Hillan, K. J., Gerber, H.-P. & Novotny, W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat. Rev. Drug Discov. 3, 391–400 (2004).

pubmed: 15136787 doi: 10.1038/nrd1381

Jain, R. K., Duda, D. G., Clark, J. W. & Loeffler, J. S. Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nat. Clin. Pract. Oncol. 3, 24–40 (2006).

pubmed: 16407877 doi: 10.1038/ncponc0403

Jabbour, A. et al. Parenteral administration of recombinant human neuregulin‐1 to patients with stable chronic heart failure produces favourable acute and chronic haemodynamic responses. Eur. J. Heart Fail. 13, 83–92 (2011).

pubmed: 20810473 doi: 10.1093/eurjhf/hfq152

Lenihan, D. J. et al. A phase I, single ascending dose study of cimaglermin alfa (Neuregulin 1β3) in patients with systolic dysfunction and heart failure. JACC Basic Transl. Sci. 1, 576–586 (2016).

pubmed: 30167542 pmcid: 6113538 doi: 10.1016/j.jacbts.2016.09.005

Winkle, P. et al. A first-in-human study of AMG 986, a novel apelin receptor agonist, in healthy subjects and heart failure patients. Cardiovasc. Drugs Ther. 37, 743–755 (2023).

pubmed: 35460392 doi: 10.1007/s10557-022-07328-w

Fontes, J. A., Rose, N. R. & Čiháková, D. The varying faces of IL-6: from cardiac protection to cardiac failure. Cytokine 74, 62–68 (2015).

pubmed: 25649043 pmcid: 4677779 doi: 10.1016/j.cyto.2014.12.024

Steffl, M. et al. Relationship between sarcopenia and physical activity in older people: a systematic review and meta-analysis. Clin. Interv. Aging 12, 835–845 (2017).

pubmed: 28553092 pmcid: 5441519 doi: 10.2147/CIA.S132940

Beckwée, D. et al. Exercise interventions for the prevention and treatment of sarcopenia. a systematic umbrella review. J. Nutr. Health Aging 23, 494–502 (2019).

pubmed: 31233069 doi: 10.1007/s12603-019-1196-8

Vlietstra, L., Hendrickx, W. & Waters, D. L. Exercise interventions in healthy older adults with sarcopenia: a systematic review and meta‐analysis. Australas. J. Ageing 37, 169–183 (2018).

pubmed: 29638028 doi: 10.1111/ajag.12521

Alves, C. R. R. et al. Exercise training reverses cancer-induced oxidative stress and decrease in muscle COPS2/TRIP15/ALIEN. Mol. Metab. 39, 101012 (2020).

pubmed: 32408015 pmcid: 7283151 doi: 10.1016/j.molmet.2020.101012

Ni, H.-J. et al. Effects of Exercise Programs in older adults with Muscle Wasting: A Systematic Review and Meta-analysis. Arch. Gerontol. Geriatr. 99, 104605 (2022).

pubmed: 34922244 doi: 10.1016/j.archger.2021.104605

Marques, E. A., Mota, J. & Carvalho, J. Exercise effects on bone mineral density in older adults: a meta-analysis of randomized controlled trials. AGE 34, 1493–1515 (2012).

pubmed: 21922251 doi: 10.1007/s11357-011-9311-8

Wolff, I., Van Croonenborg, J. J., Kemper, H. C. G., Kostense, P. J. & Twisk, J. W. R. The effect of exercise training programs on bone mass: a meta-analysis of published controlled trials in pre- and postmenopausal women. Osteoporos. Int. 9, 1–12 (1999).

pubmed: 10367023 doi: 10.1007/s001980050109

Zhang, S. et al. Effect of exercise on bone mineral density among patients with osteoporosis and osteopenia: a systematic review and network meta‐analysis. J. Clin. Nurs. 31, 2100–2111 (2022).

pubmed: 34725872 doi: 10.1111/jocn.16101

Gianola, S. et al. Effect of muscular exercise on patients with muscular dystrophy: a systematic review and meta-analysis of the literature. Front. Neurol. 11, 958 (2020).

pubmed: 33281695 pmcid: 7688624 doi: 10.3389/fneur.2020.00958

Hammer, S. et al. Exercise training in duchenne muscular dystrophy: a systematic review and meta-analysis. J. Rehabil. Med. 54, jrm00250 (2022).

pubmed: 35642324

Mendell, J. R. et al. A phase 1/2a follistatin gene therapy trial for becker muscular dystrophy. Mol. Ther. 23, 192–201 (2015).

pubmed: 25322757 doi: 10.1038/mt.2014.200

Kanzleiter, T. et al. The myokine decorin is regulated by contraction and involved in muscle hypertrophy. Biochem. Biophys. Res. Commun. 450, 1089–1094 (2014).

pubmed: 24996176 doi: 10.1016/j.bbrc.2014.06.123

Colaianni, G. et al. Irisin and bone: from preclinical studies to the evaluation of its circulating levels in different populations of human subjects. Cells 8, 451 (2019).

pubmed: 31091695 pmcid: 6562988 doi: 10.3390/cells8050451

Colaianni, G. et al. Irisin correlates positively with BMD in a cohort of older adult patients and downregulates the senescent marker P21 in osteoblasts. J. Bone Miner. Res. 36, 305–314 (2021).

pubmed: 33053231 doi: 10.1002/jbmr.4192

Zhou, K., Qiao, X., Cai, Y., Li, A. & Shan, D. Lower circulating irisin in middle-aged and older adults with osteoporosis: a systematic review and meta-analysis. Menopause 26, 1302–1310 (2019).

pubmed: 31688577 doi: 10.1097/GME.0000000000001388

Lyssikatos, C. et al. l-β-aminoisobutyric acid, L-BAIBA, a marker of bone mineral density and body mass index, and D-BAIBA of physical performance and age. Sci. Rep. 13, 17212 (2023).

pubmed: 37821627 pmcid: 10567793 doi: 10.1038/s41598-023-44249-6

Wang, Z. et al. Quantification of aminobutyric acids and their clinical applications as biomarkers for osteoporosis. Commun. Biol. 3, 39 (2020).

pubmed: 31969651 pmcid: 6976694 doi: 10.1038/s42003-020-0766-y

Falck, R. S., Davis, J. C., Best, J. R., Crockett, R. A. & Liu-Ambrose, T. Impact of exercise training on physical and cognitive function among older adults: a systematic review and meta-analysis. Neurobiol. Aging 79, 119–130 (2019).

pubmed: 31051329 doi: 10.1016/j.neurobiolaging.2019.03.007

Northey, J. M., Cherbuin, N., Pumpa, K. L., Smee, D. J. & Rattray, B. Exercise interventions for cognitive function in adults older than 50: a systematic review with meta-analysis. Br. J. Sports Med. 52, 154–160 (2018).

pubmed: 28438770 doi: 10.1136/bjsports-2016-096587

Heyn, P., Abreu, B. C. & Ottenbacher, K. J. The effects of exercise training on elderly persons with cognitive impairment and dementia: a meta-analysis. Arch. Phys. Med. Rehabil. 85, 1694–1704 (2004).

pubmed: 15468033 doi: 10.1016/j.apmr.2004.03.019

Jia, R., Liang, J., Xu, Y. & Wang, Y. Effects of physical activity and exercise on the cognitive function of patients with Alzheimer disease: a meta-analysis. BMC Geriatr. 19, 181 (2019).

pubmed: 31266451 pmcid: 6604129 doi: 10.1186/s12877-019-1175-2

Kim, R. et al. Effects of physical exercise interventions on cognitive function in Parkinson’s disease: an updated systematic review and meta-analysis of randomized controlled trials. Parkinson. Relat. Disord. 117, 105908 (2023).

doi: 10.1016/j.parkreldis.2023.105908

Kwakkel, G. et al. Effects of augmented exercise therapy time after stroke: a meta-analysis. Stroke 35, 2529–2539 (2004).

pubmed: 15472114 doi: 10.1161/01.STR.0000143153.76460.7d

Stoller, O., De Bruin, E. D., Knols, R. H. & Hunt, K. J. Effects of cardiovascular exercise early after stroke: systematic review and meta-analysis. BMC Neurol. 12, 45 (2012).

pubmed: 22727172 pmcid: 3495034 doi: 10.1186/1471-2377-12-45

Hou, L. et al. Association between physical exercise and stroke recurrence among first-ever ischemic stroke survivors. Sci. Rep. 11, 13372 (2021).

pubmed: 34183726 pmcid: 8238988 doi: 10.1038/s41598-021-92736-5

Veldema, J. & Jansen, P. Ergometer training in stroke rehabilitation: systematic review and meta-analysis. Arch. Phys. Med. Rehabil. 101, 674–689 (2020).

pubmed: 31689416 doi: 10.1016/j.apmr.2019.09.017

Veldema, J. & Jansen, P. Resistance training in stroke rehabilitation: systematic review and meta-analysis. Clin. Rehabil. 34, 1173–1197 (2020).

pubmed: 32527148 doi: 10.1177/0269215520932964

Kim, K. Y. et al. Loss of association between plasma irisin levels and cognition in Alzheimer’s disease. Psychoneuroendocrinology 136, 105624 (2022).

pubmed: 34902775 doi: 10.1016/j.psyneuen.2021.105624

Lourenco, M. V. et al. Cerebrospinal fluid irisin correlates with amyloid‐β, BDNF, and cognition in Alzheimer’s disease. Alzheimers Dement. Diagn. Assess. Dis. Monit. 12, e12034 (2020).

Zhang, X. et al. Irisin exhibits neuroprotection by preventing mitochondrial damage in Parkinson’s disease. Npj Park. Dis. 9, 13 (2023).

doi: 10.1038/s41531-023-00453-9

Moxon, J. V. et al. The effect of angiopoietin-1 upregulation on the outcome of acute ischaemic stroke in rodent models: a meta-analysis. J. Cereb. Blood Flow. Metab. 39, 2343–2354 (2019).

pubmed: 31581897 pmcid: 6893985 doi: 10.1177/0271678X19876876

Venkat, P. et al. Treatment with an angiopoietin‐1 mimetic peptide promotes neurological recovery after stroke in diabetic rats. CNS Neurosci. Ther. 27, 48–59 (2021).

pubmed: 33346402 doi: 10.1111/cns.13541

Golledge, J. et al. Plasma angiopoietin-1 is lower after ischemic stroke and associated with major disability but not stroke incidence. Stroke 45, 1064–1068 (2014).

pubmed: 24569814 doi: 10.1161/STROKEAHA.113.004339

Huuha, A. M. et al. Can exercise training teach us how to treat Alzheimer’s disease? Ageing Res. Rev. 75, 101559 (2022).

pubmed: 34999248 doi: 10.1016/j.arr.2022.101559

Tari, A. R. et al. Are the neuroprotective effects of exercise training systemically mediated? Prog. Cardiovasc. Dis. 62, 94–101 (2019).

pubmed: 30802460 doi: 10.1016/j.pcad.2019.02.003

Kim, T.-W., Park, S.-S., Park, J.-Y. & Park, H.-S. Infusion of plasma from exercised mice ameliorates cognitive dysfunction by increasing hippocampal neuroplasticity and mitochondrial functions in 3xTg-AD mice. Int. J. Mol. Sci. 21, 3291 (2020).

pubmed: 32384696 pmcid: 7247545 doi: 10.3390/ijms21093291

Tari, A. R. et al. Safety and efficacy of plasma transfusion from exercise-trained donors in patients with early Alzheimer’s disease: protocol for the ExPlas study. BMJ Open 12, e056964 (2022).

pubmed: 36538409 pmcid: 9453994 doi: 10.1136/bmjopen-2021-056964

Sha, S. J. et al. Safety, tolerability, and feasibility of young plasma infusion in the plasma for alzheimer symptom amelioration study: a randomized clinical trial. JAMA Neurol. 76, 35 (2019).

pubmed: 30383097 doi: 10.1001/jamaneurol.2018.3288

Kurz, E. et al. Exercise-induced engagement of the IL-15/IL-15Rα axis promotes anti-tumor immunity in pancreatic cancer. Cancer Cell 40, 720–737.e5 (2022).

pubmed: 35660135 pmcid: 9280705 doi: 10.1016/j.ccell.2022.05.006

San-Millán, I. & Brooks, G. A. Reexamining cancer metabolism: lactate production for carcinogenesis could be the purpose and explanation of the Warburg effect. Carcinogenesis 38, 119–133 (2017).

pubmed: 27993896

Morrell, M. B. G. et al. Vascular modulation through exercise improves chemotherapy efficacy in Ewing sarcoma. Pediatr. Blood Cancer 66, e27835 (2019).

pubmed: 31136074 pmcid: 6646082 doi: 10.1002/pbc.27835

Schadler, K. L. et al. Tumor vessel normalization after aerobic exercise enhances chemotherapeutic efficacy. Oncotarget 7, 65429–65440 (2016).

pubmed: 27589843 pmcid: 5323166 doi: 10.18632/oncotarget.11748

Pedersen, L., Christensen, J. F. & Hojman, P. Effects of exercise on tumor physiology and metabolism. Cancer J. 21, 111–116 (2015).

pubmed: 25815851 doi: 10.1097/PPO.0000000000000096

Ruiz-Casado, A. et al. Exercise and the hallmarks of cancer. Trends Cancer 3, 423–441 (2017).

pubmed: 28718417 doi: 10.1016/j.trecan.2017.04.007

Moore, S. C. et al. Association of leisure-time physical activity with risk of 26 types of cancer in 1.44 million adults. JAMA Intern. Med. 176, 816 (2016).

pubmed: 27183032 pmcid: 5812009 doi: 10.1001/jamainternmed.2016.1548

Patel, A. V. et al. American College of Sports Medicine roundtable report on physical activity, sedentary behavior, and cancer prevention and control. Med. Sci. Sports Exerc. 51, 2391–2402 (2019).

pubmed: 31626056 pmcid: 6814265 doi: 10.1249/MSS.0000000000002117

Velthuis, M. J., Agasi-Idenburg, S. C., Aufdemkampe, G. & Wittink, H. M. The effect of physical exercise on cancer-related fatigue during cancer treatment: a meta-analysis of randomised controlled trials. Clin. Oncol. 22, 208–221 (2010).

doi: 10.1016/j.clon.2009.12.005

Scott, J. M. et al. Efficacy of exercise therapy on cardiorespiratory fitness in patients with cancer: a systematic review and meta-analysis. J. Clin. Oncol. 36, 2297–2305 (2018).

pubmed: 29894274 pmcid: 6804903 doi: 10.1200/JCO.2017.77.5809

Betof, A. S., Dewhirst, M. W. & Jones, L. W. Effects and potential mechanisms of exercise training on cancer progression: a translational perspective. Brain. Behav. Immun. 30, S75–S87 (2013).

pubmed: 22610066 doi: 10.1016/j.bbi.2012.05.001

Chalmers, Z. R. et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med 9, 34 (2017).

pubmed: 28420421 pmcid: 5395719 doi: 10.1186/s13073-017-0424-2

Emery, A., Moore, S., Turner, J. E. & Campbell, J. P. Reframing how physical activity reduces the incidence of clinically-diagnosed cancers: appraising exercise-induced immuno-modulation as an integral mechanism. Front. Oncol. 12, 788113 (2022).

pubmed: 35359426 pmcid: 8964011 doi: 10.3389/fonc.2022.788113

López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

pubmed: 23746838 pmcid: 3836174 doi: 10.1016/j.cell.2013.05.039

Niccoli, T. & Partridge, L. Ageing as a risk factor for disease. Curr. Biol. 22, R741–R752 (2012).

pubmed: 22975005 doi: 10.1016/j.cub.2012.07.024

Partridge, L., Deelen, J. & Slagboom, P. E. Facing up to the global challenges of ageing. Nature 561, 45–56 (2018).

pubmed: 30185958 doi: 10.1038/s41586-018-0457-8

Hou, Y. et al. Ageing as a risk factor for neurodegenerative disease. Nat. Rev. Neurol. 15, 565–581 (2019).

pubmed: 31501588 doi: 10.1038/s41582-019-0244-7

López-Otín, C., Pietrocola, F., Roiz-Valle, D., Galluzzi, L. & Kroemer, G. Meta-hallmarks of aging and cancer. Cell Metab. 35, 12–35 (2023).

pubmed: 36599298 doi: 10.1016/j.cmet.2022.11.001

López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. Hallmarks of aging: an expanding universe. Cell 186, 243–278 (2023).

pubmed: 36599349 doi: 10.1016/j.cell.2022.11.001

Schmauck-Medina, T. et al. New hallmarks of ageing: a 2022 Copenhagen ageing meeting summary. Aging 14, 6829–6839 (2022).

pubmed: 36040386 pmcid: 9467401 doi: 10.18632/aging.204248

Garatachea, N. et al. Exercise attenuates the major hallmarks of aging. Rejuvenation Res. 18, 57–89 (2015).

pubmed: 25431878 pmcid: 4340807 doi: 10.1089/rej.2014.1623

Horowitz, A. M. & Villeda, S. A. Therapeutic potential of systemic brain rejuvenation strategies for neurodegenerative disease. F1000Research 6, 1291 (2017).

pubmed: 28815019 pmcid: 5539850 doi: 10.12688/f1000research.11437.1

Bouchard, J. & Villeda, S. A. Aging and brain rejuvenation as systemic events. J. Neurochem. 132, 5–19 (2015).

pubmed: 25327899 doi: 10.1111/jnc.12969

Villeda, S. A. et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat. Med. 20, 659–663 (2014).

pubmed: 24793238 pmcid: 4224436 doi: 10.1038/nm.3569

Villeda, S. A. et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477, 90–94 (2011).

pubmed: 21886162 pmcid: 3170097 doi: 10.1038/nature10357

Conboy, I. M. et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433, 760–764 (2005).

pubmed: 15716955 doi: 10.1038/nature03260

Sinha, M. et al. Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science 344, 649–652 (2014).

pubmed: 24797481 pmcid: 4104429 doi: 10.1126/science.1251152

Katsimpardi, L. et al. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 344, 630–634 (2014).

pubmed: 24797482 pmcid: 4123747 doi: 10.1126/science.1251141

Ho, T. T. et al. Aged hematopoietic stem cells are refractory to bloodborne systemic rejuvenation interventions. J. Exp. Med. 218, e20210223 (2021).

pubmed: 34032859 pmcid: 8155813 doi: 10.1084/jem.20210223

Van Praag, H., Shubert, T., Zhao, C. & Gage, F. H. Exercise enhances learning and hippocampal neurogenesis in aged mice. J. Neurosci. 25, 8680–8685 (2005).

pubmed: 16177036 pmcid: 1360197 doi: 10.1523/JNEUROSCI.1731-05.2005

Firth, J. et al. Effect of aerobic exercise on hippocampal volume in humans: a systematic review and meta-analysis. NeuroImage 166, 230–238 (2018).

pubmed: 29113943 doi: 10.1016/j.neuroimage.2017.11.007

Sofi, F. et al. Physical activity and risk of cognitive decline: a meta-analysis of prospective studies: physical activity and risk of cognitive decline. J. Intern. Med. 269, 107–117 (2011).

pubmed: 20831630 doi: 10.1111/j.1365-2796.2010.02281.x

Chang, Y. K., Labban, J. D., Gapin, J. I. & Etnier, J. L. The effects of acute exercise on cognitive performance: a meta-analysis. Brain Res. 1453, 87–101 (2012).

pubmed: 22480735 doi: 10.1016/j.brainres.2012.02.068

Leiter, O. & Walker, T. L. Platelets: the missing link between the blood and brain? Prog. Neurobiol. 183, 101695 (2019).

pubmed: 31550515 doi: 10.1016/j.pneurobio.2019.101695

Burnouf, T. & Walker, T. L. The multifaceted role of platelets in mediating brain function. Blood 140, 815–827 (2022).

pubmed: 35609283 pmcid: 9412009 doi: 10.1182/blood.2022015970

Bieri, G., Schroer, A. B. & Villeda, S. A. Blood-to-brain communication in aging and rejuvenation. Nat. Neurosci. 26, 379–393 (2023).

pubmed: 36646876

Brunet, A., Goodell, M. A. & Rando, T. A. Ageing and rejuvenation of tissue stem cells and their niches. Nat. Rev. Mol. Cell Biol. 24, 45–62 (2023).

pubmed: 35859206 doi: 10.1038/s41580-022-00510-w

Vargason, A. M., Anselmo, A. C. & Mitragotri, S. The evolution of commercial drug delivery technologies. Nat. Biomed. Eng. 5, 951–967 (2021).

pubmed: 33795852 doi: 10.1038/s41551-021-00698-w

Dollet, L. et al. Exercise-induced crosstalk between immune cells and adipocytes in humans: role of oncostatin-M. Cell Rep. Med. 5, 101348 (2024).

pubmed: 38151020 doi: 10.1016/j.xcrm.2023.101348

Wei, W., Raun, S. H. & Long, J. Z. Molecular insights from multiomics studies of physical activity. Diabetes 73, 162–168 (2024).

pubmed: 38241506 pmcid: 10796296 doi: 10.2337/dbi23-0004

Mittenbühler, M. J. et al. Isolation of extracellular fluids reveals novel secreted bioactive proteins from muscle and fat tissues. Cell Metab. 35, 535–549.e7 (2023).

pubmed: 36681077 pmcid: 9998376 doi: 10.1016/j.cmet.2022.12.014

Trappe, T. et al. Influence of age and resistance exercise on human skeletal muscle proteolysis: a microdialysis approach. J. Physiol. 554, 803–813 (2004).

pubmed: 14608013 doi: 10.1113/jphysiol.2003.051755

Sanford, J. A. et al. Molecular Transducers of Physical Activity Consortium (MoTrPAC): mapping the dynamic responses to exercise. Cell 181, 1464–1474 (2020).

pubmed: 32589957 pmcid: 8800485 doi: 10.1016/j.cell.2020.06.004

Noone, J., Mucinski, J. M., DeLany, J. P., Sparks, L. M. & Goodpaster, B. H. Understanding the variation in exercise responses to guide personalized physical activity prescriptions. Cell Metab. 36, 702–724 (2024).

pubmed: 38262420 doi: 10.1016/j.cmet.2023.12.025

Tanimura, Y. et al. Acute exercise increases fibroblast growth factor 21 in metabolic organs and circulation. Physiol. Rep. 4, e12828 (2016).

Zhang, H. et al. GDF15 mediates the effect of skeletal muscle contraction on glucose-stimulated insulin secretion. Diabetes 72, 1070–1082 (2023).

pubmed: 37224335 pmcid: 10382648 doi: 10.2337/db22-0019

Pedersen, B. K., Steensberg, A. & Schjerling, P. Muscle‐derived interleukin‐6: possible biological effects. J. Physiol. 536, 329–337 (2001).

pubmed: 11600669 pmcid: 2278876 doi: 10.1111/j.1469-7793.2001.0329c.xd

Steensberg, A. et al. Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6. J. Physiol. 529, 237–242 (2000).

pubmed: 11080265 pmcid: 2270169 doi: 10.1111/j.1469-7793.2000.00237.x

Haugen, F. et al. IL-7 is expressed and secreted by human skeletal muscle cells. Am. J. Physiol. Cell Physiol. 298, C807–C816 (2010).

pubmed: 20089933 doi: 10.1152/ajpcell.00094.2009

Pedersen, B. K. Muscles and their myokines. J. Exp. Biol. 214, 337–346 (2011).

pubmed: 21177953 doi: 10.1242/jeb.048074

Nishizawa, H. et al. Musclin, a novel skeletal muscle-derived secretory factor. J. Biol. Chem. 279, 19391–19395 (2004).

pubmed: 15044443 doi: 10.1074/jbc.C400066200

Pourranjbar, M. et al. Effects of aerobic exercises on serum levels of myonectin and insulin resistance in obese and overweight women. J. Med. Life 11, 381–386 (2018).

pubmed: 30894898 pmcid: 6418335 doi: 10.25122/jml-2018-0033

Arsic, N. et al. Vascular endothelial growth factor stimulates skeletal muscle regeneration in Vivo. Mol. Ther. 10, 844–854 (2004).

pubmed: 15509502 doi: 10.1016/j.ymthe.2004.08.007

Birot, O. J. G., Koulmann, N., Peinnequin, A. & Bigard, X. A. Exercise‐induced expression of vascular endothelial growth factor mRNA in rat skeletal muscle is dependent on fibre type. J. Physiol. 552, 213–221 (2003).

pubmed: 12860922 pmcid: 2343332 doi: 10.1113/jphysiol.2003.043026

Hoier, B. et al. Pro‐ and anti‐angiogenic factors in human skeletal muscle in response to acute exercise and training. J. Physiol. 590, 595–606 (2012).

pubmed: 22155930 doi: 10.1113/jphysiol.2011.216135

Gavin, T. P. et al. Angiogenic growth factor response to acute systemic exercise in human skeletal muscle. J. Appl. Physiol. 96, 19–24 (2004).

pubmed: 12949011 doi: 10.1152/japplphysiol.00748.2003

Kraus, R. M., Stallings, H. W., Yeager, R. C. & Gavin, T. P. Circulating plasma VEGF response to exercise in sedentary and endurance-trained men. J. Appl. Physiol. 96, 1445–1450 (2004).

pubmed: 14660505 doi: 10.1152/japplphysiol.01031.2003

Perakakis, N. et al. Physiology of activins/follistatins: associations with metabolic and anthropometric variables and response to exercise. J. Clin. Endocrinol. Metab. 103, 3890–3899 (2018).

pubmed: 30085147 pmcid: 6179167 doi: 10.1210/jc.2018-01056

Hansen, J. et al. Exercise induces a marked increase in plasma follistatin: evidence that follistatin is a contraction-induced hepatokine. Endocrinology 152, 164–171 (2011).

pubmed: 21068158 doi: 10.1210/en.2010-0868

Khalafi, M., Aria, B., Symonds, M. E. & Rosenkranz, S. K. The effects of resistance training on myostatin and follistatin in adults: a systematic review and meta-analysis. Physiol. Behav. 269, 114272 (2023).

pubmed: 37328021 doi: 10.1016/j.physbeh.2023.114272

Xi, Y., Gong, D.-W. & Tian, Z. FSTL1 as a potential mediator of exercise-induced cardioprotection in post-myocardial infarction rats. Sci. Rep. 6, 32424 (2016).

pubmed: 27561749 pmcid: 5000295 doi: 10.1038/srep32424

Görgens, S. W. et al. Regulation of follistatin-like protein 1 expression and secretion in primary human skeletal muscle cells. Arch. Physiol. Biochem. 119, 75–80 (2013).

pubmed: 23419164 doi: 10.3109/13813455.2013.768270

Strömberg, A. et al. CX

pubmed: 26632602 doi: 10.1152/ajpregu.00236.2015

Reza, M. M. et al. Irisin is a pro-myogenic factor that induces skeletal muscle hypertrophy and rescues denervation-induced atrophy. Nat. Commun. 8, 1104 (2017).

pubmed: 29062100 pmcid: 5653663 doi: 10.1038/s41467-017-01131-0

Roca-Rivada, A. et al. FNDC5/Irisin is not only a myokine but also an adipokine. PLoS One 8, e60563 (2013).

pubmed: 23593248 pmcid: 3623960 doi: 10.1371/journal.pone.0060563

Lee, P. et al. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab. 19, 302–309 (2014).

pubmed: 24506871 pmcid: 7647184 doi: 10.1016/j.cmet.2013.12.017

Christiansen, T. et al. Diet-induced weight loss and exercise alone and in combination enhance the expression of adiponectin receptors in adipose tissue and skeletal muscle, but only diet-induced weight loss enhanced circulating adiponectin. J. Clin. Endocrinol. Metab. 95, 911–919 (2010).

pubmed: 19996310 doi: 10.1210/jc.2008-2505

Lim, S. et al. Insulin-sensitizing effects of exercise on adiponectin and retinol-binding protein-4 concentrations in young and middle-aged women. J. Clin. Endocrinol. Metab. 93, 2263–2268 (2008).

pubmed: 18334592 doi: 10.1210/jc.2007-2028

Kriketos, A. D. et al. Exercise increases adiponectin levels and insulin sensitivity in humans. Diabetes Care 27, 629–630 (2004).

pubmed: 14747265 doi: 10.2337/diacare.27.2.629

Boucher, J. et al. Apelin, a newly identified adipokine up-regulated by insulin and obesity. Endocrinology 146, 1764–1771 (2005).

pubmed: 15677759 doi: 10.1210/en.2004-1427

Besse-Patin, A. et al. Effect of endurance training on skeletal muscle myokine expression in obese men: identification of apelin as a novel myokine. Int. J. Obes. 38, 707–713 (2014).

doi: 10.1038/ijo.2013.158

Bae, J. Y. Aerobic exercise increases meteorin-like protein in muscle and adipose tissue of chronic high-fat diet-induced obese mice. BioMed. Res. Int. 2018, 1–8 (2018).

Feng, L. et al. Exercise training protects against heart failure via expansion of myeloid-derived suppressor cells through regulating IL-10/STAT3/S100A9 pathway. Circ. Heart Fail. 15, e008550 (2022).

pubmed: 34911348 doi: 10.1161/CIRCHEARTFAILURE.121.008550

Cabral‐Santos, C. et al. Interleukin‐10 responses from acute exercise in healthy subjects: a systematic review. J. Cell. Physiol. 234, 9956–9965 (2019).

pubmed: 30536945 doi: 10.1002/jcp.27920

Steensberg, A., Fischer, C. P., Keller, C., Møller, K. & Pedersen, B. K. IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans. Am. J. Physiol. Endocrinol. Metab. 285, E433–E437 (2003).

pubmed: 12857678 doi: 10.1152/ajpendo.00074.2003

Nieman, D. C. et al. Blood leukocyte mRNA expression for IL-10, IL-1Ra, and IL-8, but Not IL-6, increases after exercise. J. Interferon Cytokine Res. 26, 668–674 (2006).

pubmed: 16978071 doi: 10.1089/jir.2006.26.668

Pedersen, B. K., Steensberg, A. & Schjerling, P. Exercise and interleukin-6. Curr. Opin. Hematol. 8, 137–141 (2001).

pubmed: 11303145 doi: 10.1097/00062752-200105000-00002

Neves, R. V. P. et al. Dynamic not isometric training blunts osteo-renal disease and improves the sclerostin/FGF23/Klotho axis in maintenance hemodialysis patients: a randomized clinical trial. J. Appl. Physiol. 130, 508–516 (2021).

pubmed: 33242299 doi: 10.1152/japplphysiol.00416.2020

Lee, S., Kolset, S. O., Birkeland, K. I., Drevon, C. A. & Reine, T. M. Acute exercise increases syndecan-1 and -4 serum concentrations. Glycoconj. J. 36, 113–125 (2019).

pubmed: 30949875 doi: 10.1007/s10719-019-09869-z

Choi, S. H. et al. Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer’s mouse model. Science 361, eaan8821 (2018).

pubmed: 30190379 pmcid: 6149542 doi: 10.1126/science.aan8821

Griffin, É. W. et al. Aerobic exercise improves hippocampal function and increases BDNF in the serum of young adult males. Physiol. Behav. 104, 934–941 (2011).

pubmed: 21722657 doi: 10.1016/j.physbeh.2011.06.005

Mohammadzadeh, R. et al. Association of neuregulin-1β with physiological cardiac hypertrophy following acute and chronic exercise in athlete and non-athlete women. Hum. Physiol. 48, 102–107 (2022).

doi: 10.1134/S036211972201011X

Bugera, E. M., Duhamel, T. A., Peeler, J. D. & Cornish, S. M. The systemic myokine response of decorin, interleukin-6 (IL-6) and interleukin-15 (IL-15) to an acute bout of blood flow restricted exercise. Eur. J. Appl. Physiol. 118, 2679–2686 (2018).

pubmed: 30244288 doi: 10.1007/s00421-018-3995-8

Jane, D. T. et al. Evidence for the involvement of cathepsin B in skeletal myoblast differentiation. J. Cell. Biochem. 84, 520–531 (2002).

pubmed: 11813257 doi: 10.1002/jcb.10042

Jurrissen, T. J. et al. Role of adropin in arterial stiffening associated with obesity and type 2 diabetes. Am. J. Physiol. Heart Circ. Physiol. 323, H879–H891 (2022).

pubmed: 36083795 pmcid: 9602697 doi: 10.1152/ajpheart.00385.2022

Fujie, S. et al. Aerobic exercise training-induced changes in serum adropin level are associated with reduced arterial stiffness in middle-aged and older adults. Am. J. Physiol. Heart Circ. Physiol. 309, H1642–H1647 (2015).

pubmed: 26371163 doi: 10.1152/ajpheart.00338.2015

Wei, J. et al. Physical exercise modulates the microglial complement pathway in mice to relieve cortical circuitry deficits induced by mutant human TDP-43. Cell Rep. 42, 112240 (2023).

pubmed: 36924491 doi: 10.1016/j.celrep.2023.112240

Campisi, J. et al. Habitual physical activity facilitates stress-induced HSP72 induction in brain, peripheral, and immune tissues. Am. J. Physiol. -Regul. Integr. Comp. Physiol. 284, R520–R530 (2003).

pubmed: 12399251 doi: 10.1152/ajpregu.00513.2002

Morton, J. P., Kayani, A. C., McArdle, A. & Drust, B. The exercise-induced stress response of skeletal muscle, with specific emphasis on humans. Sports Med. 39, 643–662 (2009).

pubmed: 19769414 doi: 10.2165/00007256-200939080-00003

Joisten, N. et al. Exercise and the Kynurenine pathway: Current state of knowledge and results from a randomized cross-over study comparing acute effects of endurance and resistance training. Exerc. Immunol. Rev. 20, 24–42 (2020).

Elrod, J. W., Calvert, J. W., Gundewar, S., Bryan, N. S. & Lefer, D. J. Nitric oxide promotes distant organ protection: evidence for an endocrine role of nitric oxide. Proc. Natl Acad. Sci. 105, 11430–11435 (2008).

pubmed: 18685092 pmcid: 2516252 doi: 10.1073/pnas.0800700105

Sahlin, K. et al. Ultraendurance exercise increases the production of reactive oxygen species in isolated mitochondria from human skeletal muscle. J. Appl. Physiol. 108, 780–787 (2010).

pubmed: 20110545 pmcid: 2853199 doi: 10.1152/japplphysiol.00966.2009

Rogers, P. J. et al. Catecholamine metabolic pathways and exercise training. Plasma and urine catecholamines, metabolic enzymes, and chromogranin-A. Circulation 84, 2346–2356 (1991).

pubmed: 1959190 doi: 10.1161/01.CIR.84.6.2346

Jorfeldt, L., Juhlin-Dannfelt, A. & Karlsson, J. Lactate release in relation to tissue lactate in human skeletal muscle during exercise. J. Appl. Physiol. 44, 350–352 (1978).

pubmed: 632175 doi: 10.1152/jappl.1978.44.3.350

Siqueira, I. R., Palazzo, R. P. & Cechinel, L. R. Circulating extracellular vesicles delivering beneficial cargo as key players in exercise effects. Free Radic. Biol. Med. 172, 273–285 (2021).

pubmed: 34119583 doi: 10.1016/j.freeradbiomed.2021.06.007

Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9, 654–659 (2007).

pubmed: 17486113 doi: 10.1038/ncb1596

Baggish, A. L. et al. Dynamic regulation of circulating microRNA during acute exhaustive exercise and sustained aerobic exercise training. J. Physiol. 589, 3983–3994 (2011).

pubmed: 21690193 pmcid: 3179997 doi: 10.1113/jphysiol.2011.213363

Chen, J. et al. Aerobic exercise suppresses cognitive injury in patients with Alzheimer’s disease by regulating long non-coding RNA TUG1. Neurosci. Lett. 826, 137732 (2024).

pubmed: 38490634 doi: 10.1016/j.neulet.2024.137732

Cai, T.-Q. et al. Role of GPR81 in lactate-mediated reduction of adipose lipolysis. Biochem. Biophys. Res. Commun. 377, 987–991 (2008).

pubmed: 18952058 doi: 10.1016/j.bbrc.2008.10.088

Liu, C. et al. Lactate inhibits lipolysis in fat cells through activation of an orphan G-protein-coupled receptor, GPR81. J. Biol. Chem. 284, 2811–2822 (2009).

pubmed: 19047060 doi: 10.1074/jbc.M806409200

Henstridge, D. C. et al. Activating HSP72 in rodent skeletal muscle increases mitochondrial number and oxidative capacity and decreases insulin resistance. Diabetes 63, 1881–1894 (2014).

pubmed: 24430435 pmcid: 4030108 doi: 10.2337/db13-0967

Park, H.-S. Hsp72 functions as a natural inhibitory protein of c-Jun N-terminal kinase. EMBO J. 20, 446–456 (2001).

pubmed: 11157751 pmcid: 133486 doi: 10.1093/emboj/20.3.446

Parcellier, A. et al. HSP27 is a ubiquitin-binding protein involved in i-Kbα proteasomal degradation. Mol. Cell. Biol. 23, 5790–5802 (2003).

pubmed: 12897149 pmcid: 166315 doi: 10.1128/MCB.23.16.5790-5802.2003

Park, K.-J., Gaynor, R. B. & Kwak, Y. T. Heat shock protein 27 association with the iκb kinase complex regulates tumor necrosis factor α-induced NF-κB activation. J. Biol. Chem. 278, 35272–35278 (2003).

pubmed: 12829720 doi: 10.1074/jbc.M305095200

Francis, S. H., Busch, J. L. & Corbin, J. D. cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action. Pharmacol. Rev. 62, 525–563 (2010).

pubmed: 20716671 pmcid: 2964902 doi: 10.1124/pr.110.002907

Kojda, G., Cheng, Y. C., Burchfield, J. & Harrison, D. G. Dysfunctional regulation of endothelial nitric oxide synthase (eNOS) expression in response to exercise in mice lacking one eNOS gene. Circulation 103, 2839–2844 (2001).

pubmed: 11401942 doi: 10.1161/01.CIR.103.23.2839

Van Meijel, L. A. et al. Effect of lactate administration on cerebral blood flow during hypoglycemia in people with type 1 diabetes. BMJ Open Diabetes Res. Care 10, e002401 (2022).

pubmed: 35321886 pmcid: 8943734 doi: 10.1136/bmjdrc-2021-002401

Charles, E. D. et al. Pegbelfermin (BMS‐986036), PEGylated FGF21, in patients with obesity and type 2 diabetes: results from a randomized phase 2 study. Obesity 27, 41–49 (2019).

pubmed: 30520566 doi: 10.1002/oby.22344

Talukdar, S. et al. A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects. Cell Metab. 23, 427–440 (2016).

pubmed: 26959184 doi: 10.1016/j.cmet.2016.02.001

Kim, A. M. et al. Once‐weekly administration of a long‐acting fibroblast growth factor 21 analogue modulates lipids, bone turnover markers, blood pressure and body weight differently in obese people with hypertriglyceridaemia and in non‐human primates. Diabetes Obes. Metab. 19, 1762–1772 (2017).

pubmed: 28573777 doi: 10.1111/dom.13023

Gaich, G. et al. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab. 18, 333–340 (2013).

pubmed: 24011069 doi: 10.1016/j.cmet.2013.08.005

Parry-Jones, A. R. et al. Phase II randomised, placebo-controlled, clinical trial of interleukin-1 receptor antagonist in intracerebral haemorrhage: BLOcking the Cytokine IL-1 in ICH (BLOC-ICH). Eur. Stroke J. 8, 819–827 (2023).

pubmed: 37452707 pmcid: 10472954 doi: 10.1177/23969873231185208

Shi, C.-X. et al. β-aminoisobutyric acid attenuates hepatic endoplasmic reticulum stress and glucose/lipid metabolic disturbance in mice with type 2 diabetes. Sci. Rep. 6, 21924 (2016).

pubmed: 26907958 pmcid: 4764829 doi: 10.1038/srep21924

Klein, A. B. et al. Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise. Nat. Commun. 12, 1041 (2021).

pubmed: 33589633 pmcid: 7884842 doi: 10.1038/s41467-021-21309-x

Molecular insights of exercise therapy in disease prevention and treatment.

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David Walzik (D)

Tiffany Y Wences Chirino (TY)

Philipp Zimmer (P)

Niklas Joisten (N)

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