Myostatin gene invalidation does not prevent skeletal muscle mass loss during experimental sepsis in mice.
experimental sepsis
muscle atrophy
muscle strength
myostatin
proteolysis
Journal
The Journal of physiology
ISSN: 1469-7793
Titre abrégé: J Physiol
Pays: England
ID NLM: 0266262
Informations de publication
Date de publication:
15 May 2024
15 May 2024
Historique:
received:
27
06
2023
accepted:
26
04
2024
medline:
15
5
2024
pubmed:
15
5
2024
entrez:
15
5
2024
Statut:
aheadofprint
Résumé
Loss of muscle mass and function induced by sepsis contributes to physical inactivity and disability in intensive care unit patients. Limiting skeletal muscle deconditioning may thus be helpful in reducing the long-term effect of muscle wasting in patients. We tested the hypothesis that invalidation of the myostatin gene, which encodes a powerful negative regulator of skeletal muscle mass, could prevent or attenuate skeletal muscle wasting and improve survival of septic mice. Sepsis was induced by caecal ligature and puncture (CLP) in 13-week-old C57BL/6J wild-type and myostatin knock-out male mice. Survival rates were similar in wild-type and myostatin knock-out mice seven days after CLP. Loss in muscle mass was also similar in wild-type and myostatin knock-out mice 4 and 7 days after CLP. The loss in muscle mass was molecularly supported by an increase in the transcript level of E3-ubiquitin ligases and autophagy-lysosome markers. This transcriptional response was blunted in myostatin knock-out mice. No change was observed in the protein level of markers of the anabolic insulin/IGF1-Akt-mTOR pathway. Muscle strength was similarly decreased in wild-type and myostatin knock-out mice 4 and 7 days after CLP. This was associated with a modified expression of genes involved in ion homeostasis and excitation-contraction coupling, suggesting that a long-term functional recovery following experimental sepsis may be impaired by a dysregulated expression of molecular determinants of ion homeostasis and excitation-contraction coupling. In conclusion, myostatin gene invalidation does not provide any benefit in preventing skeletal muscle mass loss and strength in response to experimental sepsis. KEY POINTS: Survival rates are similar in wild-type and myostatin knock-out mice seven days after the induction of sepsis. Loss in muscle mass and muscle strength are similar in wild-type and myostatin knock-out mice 4 and 7 days after the induction of an experimental sepsis. Despite evidence of a transcriptional regulation, the protein level of markers of the anabolic insulin/IGF1-Akt-mTOR pathway remained unchanged. RT-qPCR analysis of autophagy-lysosome pathway markers indicates that activity of the pathway may be altered by experimental sepsis in wild-type and myostatin knock-out mice. Experimental sepsis induces greater variations in the mRNA levels of wild-type mice than those of myostatin knock-out mice, without providing any significant catabolic resistance or functional benefits.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Société Française d'anesthésie Réanimation (SFAR)
Informations de copyright
© 2024 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.
Références
Ali, N. A., O'Brien, J. M., Hoffmann, S. P., Phillips, G., Garland, A., Finley, J. C. W., Almoosa, K., Hejal, R., Wolf, K. M., Lemeshow, S., Connors, A. F., & Marsh, C. B. (2008). Acquired weakness, handgrip strength, and mortality in critically ill patients. American Journal of Respiratory and Critical Care Medicine, 178(3), 261–268.
Amirouche, A., Durieux, A.‐C., Banzet, S., Koulmann, N., Bonnefoy, R., Mouret, C., Bigard, X., Peinnequin, A., & Freyssenet, D. (2009). Down‐regulation of Akt/mammalian target of rapamycin signaling pathway in response to myostatin overexpression in skeletal muscle. Endocrinology, 150(1), 286–294.
Brugarolas, J., Lei, K., Hurley, R. L., Manning, B. D., Reiling, J. H., Hafen, E., Witters, L. A., Ellisen, L. W., & Kaelin, W. G. (2004). Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes & Development, 18(23), 2893–2904.
Cacciani, N., Skärlén, Å., Wen, Y., Zhang, X., Addinsall, A. B., Llano‐Diez, M., Li, M., Gransberg, L., Hedström, Y., Bellander, B.‐M., Nelson, D., Bergquist, J., & Larsson, L. (2022). A prospective clinical study on the mechanisms underlying critical illness myopathy‐A time‐course approach. Journal of Cachexia Sarcopenia Muscle, 13(6), 2669–2682.
Constantin, D., Mccullough, J., Mahajan, R P., & Greenhaff, P. L. (2011). Novel events in the molecular regulation of muscle mass in critically ill patients. The Journal of Physiology, 589(15), 3883–3895.
Crossland, H., Constantin‐Teodosiu, D., Gardiner, S. M., Constantin, D., & Greenhaff, P. L. (2008). A potential role for Akt/FOXO signalling in both protein loss and the impairment of muscle carbohydrate oxidation during sepsis in rodent skeletal muscle. The Journal of Physiology, 586(22), 5589–5600.
Desgeorges, M. M., Devillard, X., Toutain, J., Divoux, D., Castells, J., Bernaudin, M., Touzani, O., & Freyssenet, D. G. (2015). Molecular mechanisms of skeletal muscle atrophy in a mouse model of cerebral ischemia. Stroke; A Journal of Cerebral Circulation, 46(6), 1673–1680.
Durieux, A.‐C., Amirouche, A., Banzet, S., Koulmann, N., Bonnefoy, R., Pasdeloup, M., Mouret, C., Bigard, X., Peinnequin, A., & Freyssenet, D. (2007). Ectopic expression of myostatin induces atrophy of adult skeletal muscle by decreasing muscle gene expression. Endocrinology, 148(7), 3140–3147.
Fareed, M. U., Evenson, A. R., Wei, W., Menconi, M., Poylin, V., Petkova, V., Pignol, B., & Hasselgren, P.‐O. (2006). Treatment of rats with calpain inhibitors prevents sepsis‐induced muscle proteolysis independent of atrogin‐1/MAFbx and MuRF1 expression. American Journal of Physiology‐Regulatory, Integrative and Comparative Physiology, 290(6), R1589–R1597.
Friedrich, O., Reid, M. B., Van Den Berghe, G., Vanhorebeek, I., Hermans, G., Rich, M. M., & Larsson, L. (2015). The sick and the weak: Neuropathies/myopathies in the critically Ill. Physiological Reviews, 95(3), 1025–1109.
Gallot, Y. S., Durieux, A.‐C., Castells, J., Desgeorges, M. M., Vernus, B., Plantureux, L., Rémond, D., Jahnke, V. E., Lefai, E., Dardevet, D., Nemoz, G., Schaeffer, L., Bonnieu, A., & Freyssenet, D. G. (2014). Myostatin gene inactivation prevents skeletal muscle wasting in cancer. Cancer Research, 74(24), 7344–7356.
Grobet, L., Pirottin, D., Farnir, F., Poncelet, D., Royo, L. J., Brouwers, B., Christians, E., Desmecht, D., Coignoul, F., Kahn, R., & Georges, M. (2003). Modulating skeletal muscle mass by postnatal, muscle‐specific inactivation of the myostatin gene. Genesis (New York, N.Y.: 2000), 35(4), 227–238.
Grunow, J. J., Reiher, K., Carbon, N. M., Engelhardt, L. J., Mai, K., Koch, S., Schefold, J. C., Z'graggen, W., Schaller, S. J., Fielitz, J., Spranger, J., Weber‐Carstens, S., & Wollersheim, T. (2022). Muscular myostatin gene expression and plasma concentrations are decreased in critically ill patients. Critical Care (London, England), 26(1), 237.
Herridge, M. S., Cheung, A. M., Tansey, C M., Matte‐Martyn, A., Diaz‐Granados, N., Al‐Saidi, F., Cooper, A B., Guest, C. B., Mazer, C. D, Mehta, S., Stewart, T E., Barr, A., Cook, D., & Slutsky, A. S. (2003). One‐year outcomes in survivors of the acute respiratory distress syndrome. New England Journal of Medicine, 348(8), 683–693.
Hill, N. E., Saeed, S., Phadke, R., Ellis, M. J., Chambers, D., Wilson, D. R., Castells, J., Morel, J., Freysennet, D. G., Brett, S. J., Murphy, K. G., & Singer, M. (2015). Detailed characterization of a long‐term rodent model of critical illness and recovery. Critical Care Medicine, 43(3), e84–e96.
Hotchkiss, R S., Monneret, G., & Payen, D. (2013). Sepsis‐induced immunosuppression: From cellular dysfunctions to immunotherapy. Nature Reviews Immunology, 13(12), 862–874.
Klaude, M., Mori, M., Tjäder, I., Gustafsson, T., Wernerman, J., & Rooyackers, O. (2012). Protein metabolism and gene expression in skeletal muscle of critically ill patients with sepsis. Clinical Science (London, England: 1979), 122(3), 133–142.
Kobayashi, M., Kasamatsu, S., Shinozaki, S., Yasuhara, S., & Kaneki, M. (2021). Myostatin deficiency not only prevents muscle wasting but also improves survival in septic mice. American Journal of Physiology‐Endocrinology and Metabolism, 320(1), E150–E159.
Latres, E., Mastaitis, J., Fury, W., Miloscio, L., Trejos, J., Pangilinan, J., Okamoto, H., Cavino, K., Na, E., Papatheodorou, A., Willer, T., Bai, Y., Hae Kim, J., Rafique, A., Jaspers, S., Stitt, T., Murphy, A. J., Yancopoulos, G. D., & Gromada, J. (2017). Activin A more prominently regulates muscle mass in primates than does GDF8. Nature Communications, 8(1), 15153.
Latronico, N., & Bolton, C. F (2011). Critical illness polyneuropathy and myopathy: A major cause of muscle weakness and paralysis. Lancet Neurology, 10(10), 931–941.
Lee, S.‐J. (2023). Myostatin: A skeletal muscle chalone. Annual Review of Physiology, 85(1), 269–291.
Mariot, V., Joubert, R., Hourdé, C., Féasson, L., Hanna, M., Muntoni, F., Maisonobe, T., Servais, L., Bogni, C., Le Panse, R., Benvensite, O., Stojkovic, T., Machado, P. M., Voit, T., Buj‐Bello, A., & Dumonceaux, J. (2017). Downregulation of myostatin pathway in neuromuscular diseases may explain challenges of anti‐myostatin therapeutic approaches. Nature Communications, 8(1), 1859.
Mcpherron, A. C., Lawler, A. M., & Lee, S.‐J. (1997). Regulation of skeletal muscle mass in mice by a new TGF‐beta superfamily member. Nature, 387(6628), 83–90.
Mofarrahi, M., Sigala, I., Guo, Y., Godin, R., Davis, E. C., Petrof, B., Sandri, M., Burelle, Y., & Hussain, S. N. A. (2012). Autophagy and skeletal muscles in sepsis. PLoS One, 7(10), e47265.
Morel, J., Palao, J.‐C., Castells, J., Desgeorges, M., Busso, T., Molliex, S., Jahnke, V., Del Carmine, P., Gondin, J., Arnould, D., Durieux, A. C., & Freyssenet, D. (2017). Regulation of Akt‐mTOR, ubiquitin‐proteasome and autophagy‐lysosome pathways in locomotor and respiratory muscles during experimental sepsis in mice. Scientific Reports, 7(1), 10866.
Owen, A. M., Patel, S. P., Smith, J. D., Balasuriya, B. K., Mori, S. F., Hawk, G. S., Stromberg, A. J., Kuriyama, N., Kaneki, M., Rabchevsky, A. G., Butterfield, T. A., Esser, K. A., Peterson, C. A., Starr, M. E., & Saito, H. (2019). Chronic muscle weakness and mitochondrial dysfunction in the absence of sustained atrophy in a preclinical sepsis model. Elife, 8, e49920.
Puthucheary, Z. A., Rawal, J., Mcphail, M., Connolly, B., Ratnayake, G., Chan, P., Hopkinson, N. S., Padhke, R., Dew, T., Sidhu, P. S., Velloso, C., Seymour, J., Agley, C. C., Selby, A., Limb, M., Edwards, L. M., Smith, K., Rowlerson, A., Rennie, M. J., Moxham, J., Harridge, S. D. R., Hart, N., & Montgomery, H. E. (2013). Acute skeletal muscle wasting in critical illness. Journal of the American Medical Association, 310(15), 1591–1600.
Schefold, J. C., Bierbrauer, J., & Weber‐Carstens, S. (2010). Intensive care unit‐acquired weakness (ICUAW) and muscle wasting in critically ill patients with severe sepsis and septic shock. Journal of Cachexia Sarcopenia Muscle, 1(2), 147–157.
Schuelke, M., Wagner, K. R., Stolz, L. E., Hübner, C., Riebel, T., Kömen, W., Braun, T., Tobin, J. F., & Lee, S.‐J. (2004). Myostatin mutation associated with gross muscle hypertrophy in a child. New England Journal of Medicine, 350(26), 2682–2688.
Schweickert, W. D., Patel, B. K., & Kress, J. P. (2022). Timing of early mobilization to optimize outcomes in mechanically ventilated ICU patients. Intensive Care Medicine, 48(10), 1305–1307.
Voisin, L., Breuillé, D., Combaret, L., Pouyet, C., Taillandier, D., Aurousseau, E., Obled, C., & Attaix, D. (1996). Muscle wasting in a rat model of long‐lasting sepsis results from the activation of lysosomal, Ca2+‐activated, and ubiquitin‐proteasome proteolytic pathways. Journal of Clinical Investigation, 97(7), 1610–1617.
Wei, W., Fareed, M. U., Evenson, A., Menconi, M. J., Yang, H., Petkova, V., & Hasselgren, P.‐O. (2005). Sepsis stimulates calpain activity in skeletal muscle by decreasing calpastatin activity but does not activate caspase‐3. American Journal of Physiology‐Regulatory, Integrative and Comparative Physiology, 288(3), R580–R590.
Wilkes, J J., Lloyd, D. J., & Gekakis, N. (2009). Loss‐of‐function mutation in myostatin reduces tumor necrosis factor alpha production and protects liver against obesity‐induced insulin resistance. Diabetes, 58(5), 1133–1143.
Wirtz, T. H., Loosen, S. H., Buendgens, L., Kurt, B., Abu Jhaisha, S., Hohlstein, P., Brozat, J. F., Weiskirchen, R., Luedde, T., Tacke, F., Trautwein, C., Roderburg, C., & Koch, A. (2020). Low myostatin serum levels are associated with poor outcome in critically ill patients. Diagnostics (Basel), 10, 574.
Wollersheim, T., Woehlecke, J., Krebs, M., Hamati, J., Lodka, D., Luther‐Schroeder, A., Langhans, C., Haas, K., Radtke, T., Kleber, C., Spies, C., Labeit, S., Schuelke, M., Spuler, S., Spranger, J., Weber‐Carstens, S., & Fielitz, J. (2014). Dynamics of myosin degradation in intensive care unit‐acquired weakness during severe critical illness. Intensive Care Medicine, 40(4), 528–538.
Zhang, L., Rajan, V., Lin, E., Hu, Z., Han, H. Q., Zhou, X., Song, Y., Min, H., Wang, X., Du, J., & Mitch, W. E. (2011). Pharmacological inhibition of myostatin suppresses systemic inflammation and muscle atrophy in mice with chronic kidney disease. Federation of American Societies for Experimental Biology Journal, 25(5), 1653–1663.
Zhou, X., Wang, J. L., Lu, J., Song, Y., Kwak, K. S., Jiao, Q., Rosenfeld, R., Chen, Q., Boone, T., Simonet, W. S, Lacey, D. L., Goldberg, A. L., & Han, H. Q. (2010). Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival. Cell, 142(4), 531–543.