Identification of nicotinamide N-methyltransferase as a promising therapeutic target for sarcopenia.
NAD+
NNMT
diagnostic biomarker
metabolic dysregulation
sarcopenia
Journal
Aging cell
ISSN: 1474-9726
Titre abrégé: Aging Cell
Pays: England
ID NLM: 101130839
Informations de publication
Date de publication:
05 Jun 2024
05 Jun 2024
Historique:
revised:
18
05
2024
received:
27
11
2023
accepted:
20
05
2024
medline:
5
6
2024
pubmed:
5
6
2024
entrez:
5
6
2024
Statut:
aheadofprint
Résumé
Sarcopenia is a significant geriatric syndrome that involves the loss of skeletal muscle mass and strength. Due to its substantial endocrine role, the metabolic microenvironment of skeletal muscle undergoes changes with age. Examining the pathogenesis of sarcopenia through focusing on metabolic dysregulation could offer insights for developing more effective intervention strategies. In this study, we analyzed the transcriptomics data to identify specific genes involved in the regulation of metabolism in skeletal muscle during the development of sarcopenia. Three machine learning algorithms were employed to screen key target genes exhibiting strong correlations with metabolism, which were further validated using RNA-sequencing data and publicly accessible datasets. Among them, the metabolic enzyme nicotinamide N-methyltransferase (NNMT) was elevated in sarcopenia, and predicted sarcopenia with an area under the curve exceeding 0.7, suggesting it as a potential therapeutic target for sarcopenia. As expected, inhibition of NNMT improved the grip strength in aging mice and alleviated age-related decline in the mass index of the quadriceps femoris muscles and whole-body lean mass index. Additionally, the NNMTi treatment increased the levels of nicotinamide adenine dinucleotide (NAD
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e14236Subventions
Organisme : Grants from the Chinese National Science & Technology Pillar Program
ID : 2020YFC2005600
Organisme : Sichuan Science and Technology Program
ID : 2022ZDZX0021
Organisme : Sichuan Science and Technology Program
ID : 2023ZYD0173
Organisme : Sichuan Science and Technology Program
ID : 2024YFHZ0072
Organisme : 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University
ID : ZYJC21005
Organisme : National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University
ID : Z2023JC004
Organisme : Project funded by China Postdoctoral Science Foundation
ID : 2022M712253
Organisme : Health Research of Cadres in Sichuan province
ID : SCR2022-101
Organisme : Science and Technology Project of Sichuan Province
ID : 2023NSFSC1525
Organisme : West China Hospital Postdoctoral Foundation
ID : YN20230767
Informations de copyright
© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.
Références
Al Saedi, A., Debruin, D. A., Hayes, A., & Hamrick, M. (2022). Lipid metabolism in sarcopenia. Bone, 164, 116539. https://doi.org/10.1016/j.bone.2022.116539
Azman, K. F., & Zakaria, R. (2019). D‐galactose‐induced accelerated aging model: An overview. Biogerontology, 20(6), 763–782. https://doi.org/10.1007/s10522‐019‐09837‐y
Covarrubias, A. J., Perrone, R., Grozio, A., & Verdin, E. (2021). NAD+ metabolism and its roles in cellular processes during ageing. Nature Reviews. Molecular Cell Biology, 22(2), 119–141. https://doi.org/10.1038/s41580‐020‐00313‐x
Cruz‐Jentoft, A. J., Baeyens, J. P., Bauer, J. M., Boirie, Y., Cederholm, T., Landi, F., Martin, F. C., Michel, J. P., Rolland, Y., Schneider, S. M., Topinková, E., Vandewoude, M., & Zamboni, M. (2010). Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age and Ageing, 39(4), 412–423. https://doi.org/10.1093/ageing/afq034
Daily, J. W., & Park, S. (2022). Sarcopenia is a cause and consequence of metabolic dysregulation in aging humans: Effects of gut dysbiosis, glucose dysregulation, diet and lifestyle. Cells, 11(3), 338. https://doi.org/10.3390/cells11030338
Gao, Y., Martin, N. I., & van Haren, M. J. (2021). Nicotinamide N‐methyl transferase (NNMT): An emerging therapeutic target. Drug Discovery Today, 26(11), 2699–2706. https://doi.org/10.1016/j.drudis.2021.05.011
Gueugneau, M., Coudy‐Gandilhon, C., Chambon, C., Verney, J., Taillandier, D., Combaret, L., Polge, C., Walrand, S., Roche, F., Barthélémy, J. C., Féasson, L., & Béchet, D. (2021). Muscle proteomic and transcriptomic profiling of healthy aging and metabolic syndrome in men. International Journal of Molecular Sciences, 22(8), 4205. https://doi.org/10.3390/ijms22084205
Kannt, A., Pfenninger, A., Teichert, L., Tönjes, A., Dietrich, A., Schön, M. R., Klöting, N., & Blüher, M. (2015). Association of nicotinamide‐N‐methyltransferase mRNA expression in human adipose tissue and the plasma concentration of its product, 1‐methylnicotinamide, with insulin resistance. Diabetologia, 58(4), 799–808. https://doi.org/10.1007/s00125‐014‐3490‐7
Komatsu, M., Kanda, T., Urai, H., Kurokochi, A., Kitahama, R., Shigaki, S., Ono, T., Yukioka, H., Hasegawa, K., Tokuyama, H., Kawabe, H., Wakino, S., & Itoh, H. (2018). NNMT activation can contribute to the development of fatty liver disease by modulating the NAD+ metabolism. Scientific Reports, 8(1), 8637. https://doi.org/10.1038/s41598‐018‐26882‐8
Lafoux, A., Lotteau, S., Huchet, C., & Ducreux, S. (2020). The contractile phenotype of skeletal muscle in TRPV1 knockout mice is gender‐specific and exercise‐dependent. Life (Basel), 10(10), 233. https://doi.org/10.3390/life10100233
Leek, J. T. (2014). Svaseq: Removing batch effects and other unwanted noise from sequencing data. Nucleic Acids Research, 42(21), e161. https://doi.org/10.1093/nar/gku864
Leek, J. T., Johnson, W. E., Parker, H. S., Jaffe, A. E., & Storey, J. D. (2012). The sva package for removing batch effects and other unwanted variation in high‐throughput experiments. Bioinformatics, 28(6), 882–883. https://doi.org/10.1093/bioinformatics/bts034
Liccini, A., & Malmstrom, T. K. (2016). Frailty and sarcopenia as predictors of adverse health outcomes in persons with diabetes mellitus. Journal of the American Medical Directors Association, 17(9), 846–851. https://doi.org/10.1016/j.jamda.2016.07.007
Liu, J. R., Deng, Z. H., Zhu, X. J., Zeng, Y. R., Guan, X. X., & Li, J. H. (2021). Roles of nicotinamide N‐methyltransferase in obesity and type 2 diabetes. BioMed Research International, 2021, 9924314. https://doi.org/10.1155/2021/9924314
Liu, X., & Yue, J. (2022). Precision intervention for sarcopenia. Precision Clinical Medicine, 5(2), pbac013. https://doi.org/10.1093/pcmedi/pbac013
Long, K., Su, D., Li, X., Li, H., Zeng, S., Zhang, Y., Zhong, Z., Lin, Y., Li, X., Lu, L., Jin, L., Ma, J., Tang, Q., & Li, M. (2022). Identification of enhancers responsible for the coordinated expression of myosin heavy chain isoforms in skeletal muscle. BMC Genomics, 23(1), 519. https://doi.org/10.1186/s12864‐022‐08737‐9
Manickam, R., Tur, J., Badole, S. L., Chapalamadugu, K. C., Sinha, P., Wang, Z., Russ, D. W., Brotto, M., & Tipparaju, S. M. (2022). Nampt activator P7C3 ameliorates diabetes and improves skeletal muscle function modulating cell metabolism and lipid mediators. Journal of Cachexia, Sarcopenia and Muscle, 13(2), 1177–1196. https://doi.org/10.1002/jcsm.12887
Mellen, R. H., Girotto, O. S., Marques, E. B., Laurindo, L. F., Grippa, P. C., Mendes, C. G., Garcia, L. N. H., Bechara, M. D., Barbalho, S. M., Sinatora, R. V., Haber, J., Flato, U. A. P., Bueno, P., Detregiachi, C. R. P., & Quesada, K. (2023). Insights into pathogenesis, nutritional and drug approach in Sarcopenia: A systematic review. Biomedicine, 11(1), 136. https://doi.org/10.3390/biomedicines11010136
Migliavacca, E., Tay, S. K. H., Patel, H. P., Sonntag, T., Civiletto, G., McFarlane, C., Forrester, T., Barton, S. J., Leow, M. K., Antoun, E., Charpagne, A., Seng Chong, Y., Descombes, P., Feng, L., Francis‐Emmanuel, P., Garratt, E. S., Giner, M. P., Green, C. O., Karaz, S., … Feige, J. N. (2019). Mitochondrial oxidative capacity and NAD+ biosynthesis are reduced in human sarcopenia across ethnicities. Nature Communications, 10(1), 5808. https://doi.org/10.1038/s41467‐019‐13694‐1
Mills, K. F., Yoshida, S., Stein, L. R., Grozio, A., Kubota, S., Sasaki, Y., Redpath, P., Migaud, M. E., Apte, R. S., Uchida, K., Yoshino, J., & Imai, S. I. (2016). Long‐term Administration of nicotinamide mononucleotide mitigates age‐associated physiological decline in mice. Cell Metabolism, 24(6), 795–806. https://doi.org/10.1016/j.cmet.2016.09.013
Nations U. (2022). World population prospects 2022. United Nations. https://www.un.org/development/desa/pd/content/World‐Population‐Prospects‐2022
Neelakantan, H., Brightwell, C. R., Graber, T. G., Maroto, R., Wang, H. L., McHardy, S. F., Papaconstantinou, J., Fry, C. S., & Watowich, S. J. (2019). Small molecule nicotinamide N‐methyltransferase inhibitor activates senescent muscle stem cells and improves regenerative capacity of aged skeletal muscle. Biochemical Pharmacology, 163, 481–492. https://doi.org/10.1016/j.bcp.2019.02.008
Papadopoulou, S. K., Tsintavis, P., Potsaki, P., & Papandreou, D. (2020). Differences in the prevalence of sarcopenia in community‐dwelling, nursing home and hospitalized individuals. A systematic review and meta‐analysis. The Journal of Nutrition, Health & Aging, 24(1), 83–90. https://doi.org/10.1007/s12603‐019‐1267‐x
Petermann‐Rocha, F., Balntzi, V., Gray, S. R., Lara, J., Ho, F. K., Pell, J. P., & Celis‐Morales, C. (2022). Global prevalence of sarcopenia and severe sarcopenia: A systematic review and meta‐analysis. Journal of Cachexia, Sarcopenia and Muscle, 13(1), 86–99. https://doi.org/10.1002/jcsm.12783
Pissios, P. (2017). Nicotinamide N‐methyltransferase: More than a vitamin B3 clearance enzyme. Trends in Endocrinology and Metabolism, 28(5), 340–353. https://doi.org/10.1016/j.tem.2017.02.004
Ritchie, M. E., Phipson, B., Wu, D., Hu, Y., Law, C. W., Shi, W., & Smyth, G. K. (2015). Limma powers differential expression analyses for RNA‐sequencing and microarray studies. Nucleic Acids Research, 43(7), e47. https://doi.org/10.1093/nar/gkv007
Roberti, A., Fernández, A. F., & Fraga, M. F. (2021). Nicotinamide N‐methyltransferase: At the crossroads between cellular metabolism and epigenetic regulation. Molecular Metabolism, 45, 101165. https://doi.org/10.1016/j.molmet.2021.101165
Sayer, A. A., & Cruz‐Jentoft, A. (2022). Sarcopenia definition, diagnosis and treatment: Consensus is growing. Age and Ageing, 51(10), afac220. https://doi.org/10.1093/ageing/afac220
Shoemaker, M. E., Pereira, S. L., Mustad, V. A., Gillen, Z. M., McKay, B. D., Lopez‐Pedrosa, J. M., Rueda, R., & Cramer, J. T. (2022). Differences in muscle energy metabolism and metabolic flexibility between sarcopenic and nonsarcopenic older adults. Journal of Cachexia, Sarcopenia and Muscle, 13(2), 1224–1237. https://doi.org/10.1002/jcsm.12932
Trott, O., & Olson, A. J. (2010). AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry, 31(2), 455–461. https://doi.org/10.1002/jcc.21334
Wang, H. H., Zhang, Y., Qu, T. Q., Sang, X. Q., Li, Y. X., Ren, F. Z., Wen, P. C., & Sun, Y. N. (2023). Nobiletin improves D‐galactose‐induced aging mice skeletal muscle atrophy by regulating protein homeostasis. Nutrients, 15(8), 1801. https://doi.org/10.3390/nu15081801
Wang, W., Yang, C., Wang, T., & Deng, H. (2022). Complex roles of nicotinamide N‐methyltransferase in cancer progression. Cell Death & Disease, 13(3), 267. https://doi.org/10.1038/s41419‐022‐04713‐z
Wathanavasin, W., Banjongjit, A., Avihingsanon, Y., Praditpornsilpa, K., Tungsanga, K., Eiam‐Ong, S., & Susantitaphong, P. (2022). Prevalence of sarcopenia and its impact on cardiovascular events and mortality among dialysis patients: A systematic review and meta‐analysis. Nutrients, 14(19), 4077. https://doi.org/10.3390/nu14194077
Williams, K., Ingerslev, L. R., Bork‐Jensen, J., Wohlwend, M., Hansen, A. N., Small, L., Ribel‐Madsen, R., Astrup, A., Pedersen, O., Auwerx, J., Workman, C. T., Grarup, N., Hansen, T., & Barrès, R. (2020). Skeletal muscle enhancer interactions identify genes controlling whole‐body metabolism. Nature Communications, 11(1), 2695. https://doi.org/10.1038/s41467‐020‐16537‐6
Wu, Y., Wu, Y., Yang, Y., Yu, J., Wu, J., Liao, Z., Guo, A., Sun, Y., Zhao, Y., Chen, J., & Xiao, Q. (2022). Lysyl oxidase‐like 2 inhibitor rescues D‐galactose‐induced skeletal muscle fibrosis. Aging Cell, 21(7), e13659. https://doi.org/10.1111/acel.13659
Yang, Q., & Chan, P. (2022). Skeletal muscle metabolic alternation develops sarcopenia. Aging and Disease, 13(3), 801–814. https://doi.org/10.14336/ad.2021.1107
Zhang, H., Lin, S., Gao, T., Zhong, F., Cai, J., Sun, Y., & Ma, A. (2018). Association between sarcopenia and metabolic syndrome in middle‐aged and older non‐obese adults: A systematic review and meta‐analysis. Nutrients, 10(3), 364. https://doi.org/10.3390/nu10030364