Age-dependent loss of Crls1 causes myopathy and skeletal muscle regeneration failure
0
조회
0
다운로드
0
인용
0
참고문헌
초록
Skeletal muscle aging results in the gradual suppression of myogenesis, leading to muscle mass loss. However, the specific role of cardiolipin in myogenesis has not been determined. This study investigated the crucial role of mitochondrial cardiolipin and cardiolipin synthase 1 (Crls1) in age-related muscle deterioration and myogenesis. Our findings demonstrated that cardiolipin and Crls1 are downregulated in aged skeletal muscle. Moreover, the knockdown of Crls1 in myoblasts reduced mitochondrial mass, activity, and OXPHOS complex IV expression and disrupted the structure of the mitochondrial cristae. AAV9-shCrls1-mediated downregulation of Crls1 impaired muscle regeneration in a mouse model of cardiotoxin (CTX)-induced muscle damage, whereas AAV9-mCrls1-mediated Crls1 overexpression improved regeneration. Overall, our results highlight that the age-dependent decrease in CRLS1 expression contributes to muscle loss by diminishing mitochondrial quality in skeletal muscle myoblasts. Hence, modulating CRLS1 expression is a promising therapeutic strategy for mitigating muscle deterioration associated with aging, suggesting potential avenues for developing interventions to improve overall muscle health and quality of life in elderly individuals.
Abstract
Skeletal muscle aging results in the gradual suppression of myogenesis, leading to muscle mass loss. However, the specific role of cardiolipin in myogenesis has not been determined. This study investigated the crucial role of mitochondrial cardiolipin and cardiolipin synthase 1 (Crls1) in age-related muscle deterioration and myogenesis. Our findings demonstrated that cardiolipin and Crls1 are downregulated in aged skeletal muscle. Moreover, the knockdown of Crls1 in myoblasts reduced mitochondrial mass, activity, and OXPHOS complex IV expression and disrupted the structure of the mitochondrial cristae. AAV9-shCrls1-mediated downregulation of Crls1 impaired muscle regeneration in a mouse model of cardiotoxin (CTX)-induced muscle damage, whereas AAV9-mCrls1-mediated Crls1 overexpression improved regeneration. Overall, our results highlight that the age-dependent decrease in CRLS1 expression contributes to muscle loss by diminishing mitochondrial quality in skeletal muscle myoblasts. Hence, modulating CRLS1 expression is a promising therapeutic strategy for mitigating muscle deterioration associated with aging, suggesting potential avenues for developing interventions to improve overall muscle health and quality of life in elderly individuals.
참고문헌 (37)
- Frontera, W. R., "Skeletal muscle: a brief review of structure and function", Calcif. Tissue Int, 96, pp.183~195 (2015)
- Rolland, Y., "Sarcopenia : its assessment, etiology, pathogenesis, con sequences and future perspectives", J. Nutr. Health Aging, 12, pp.433~450 (2008)
- von Haehling, S., "An overview of sarcopenia : facts and numbers on prevalence and clinical impact", J. Cachexia Sarcopenia Muscle, 1, pp.129~133 (2010)
- Cohen, S., "Muscle wasting in disease : molecular mechanisms and promising therapies", Nat. Rev. Drug Discov, 14, pp.58~74 (2015)
- Leduc-Gaudet, J. P., "Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging", Int J. Mol. Sci, 22, pp.8179~ (2021)
- Lee, C. E., "The role of hormones, cytokines and heat shock proteins during age-related muscle loss", Clin. Nutr, 26, pp.524~534 (2007)
- Larsson, L., "Sarcopenia : Aging-Related Loss of Muscle Mass and Function", Physiol. Rev, 99, pp.427~511 (2019)
- Yin, L., "Skeletal muscle atrophy : From mechanisms to treatments", Pharm. Res, 172, pp.105807~ (2021)
- Sartori, R., "Mechanisms of muscle atrophy and hypertrophy : implications in health and disease", Nat. Commun, 12, pp.330~ (2021)
- Abrigo, J., "Mitochondrial Dysfunction in Skeletal Muscle Pathologies", Curr. Protein Pept. Sci, 20, pp.536~546 (2019)
- Alston, C. L., "The genetics and pathology of mitochondrial disease", J. Pathol, 241, pp.236~250 (2017)
- Hong, X., "Mitochondrial dynamics maintain muscle stem cell regenerative competence throughout adult life by regulating metabolism and mitophagy", Cell Stem Cell, 29, pp.1506~1508 (2022)
- Kojima, R., "Maintenance of Cardiolipin and Crista Structure Requires Coop erative Functions of Mitochondrial Dynamics and Phospholipid Transport", Cell Rep, 26, pp.518~528 (2019)
- Funai, K., "Reign in the membrane: How common lipids govern mitochondrial function", Curr. Opin. Cell Biol, 63, pp.162~173 (2020)
- Pennington, E. R., "The role of cardiolipin concentration and acyl chain composition on mitochondrial inner membrane molecular organization and function", Biochim Biophys. Acta Mol. Cell Biol. Lipids, 1864, pp.1039~1052 (2019)
- Dudek, J., "Role of Cardiolipin in Mitochondrial Signaling Pathways", Front Cell Dev. Biol, 5, pp.90~ (2017)
- Ren, M., "Metabolism and function of mitochondrial cardiolipin", Prog. Lipid Res, 55, pp.1~16 (2014)
- Claypool, S. M., "Cardiolipin defines the interactome of the major ADP", ATP carrier protein of the mitochon drial inner membrane, 2008, pp.182, 937~950
- Fry, M., "Cardiolipin requirement for electron transfer in complex I and III of the mitochondrial respiratory chain", J. Biol. Chem, 256, pp.1874~1880 (1981)
- Robinson, N. C., "Functional binding of cardiolipin to cytochrome c oxidase", J. Bioenerg. Biomembr, 25, pp.153~163 (1993)
- Lange, C., "Specific roles of protein phospholipid interactions in the yeast cytochrome bc1 complex structure", EMBO J, 20, pp.6591~6600 (2001)
- Ozawa, T., "Crystallization of mitochondrial cyto chrome oxidase", Proc. Natl Acad. Sci. USA, 79, pp.7175~7179 (1982)
- Lu, Y. W., "Disorders of phospholipid metabolism : an emerging class of mitochondrial disease due to defects in nuclear genes", Front Genet, 6, pp.3~ (2015)
- Ursu, D., "Excitation-contraction coupling in skeletal muscle of a mouse lacking the dihydropyridine receptor subunit gamma1", J. Physiol, 533, pp.367~377 (2001)
- Dayal, A., "The Ca(2+)influx through the mammalian skeletal muscle dihy dropyridine receptor is irrelevant for muscle performance", Nat. Commun, 8, pp.475~ (2017)
- Petrosillo, G., "Mitochon drial dysfunction in rat brain with aging Involvement of complex I, reactive oxygen species and cardiolipin", Neurochem Int, 53, pp.126~131 (2008)
- Petrosillo, G., "Decline in cyto chrome c oxidase activity in rat-brain mitochondria with aging. Role of peroxidized cardiolipin and beneficial effect of melatonin", J. Bioenerg. Biomembr, 45, pp.431~440 (2013)
- Lesnefsky, E. J., "Cardiolipin as an oxidative target in cardiac mitochondria in the aged rat", Biochim Biophys. Acta, 1777, pp.1020~1027 (2008)
- Paradies, G., "Age-dependent decline in the cytochrome c oxidase activity in rat heart mitochondria: role of cardiolipin", FEBS Lett, 406, pp.136~138 (1997)
- Paradies, G., "Role of Cardiolipin in Mitochondrial Function and Dynamics in Health and Disease: Molecular and Pharmacological Aspects", Cells, 8, pp.728~ (2019)
- Zincarelli, C., "Analysis of AAV serotypes 1-9mediated gene expression and tropism in mice after systemic injection", Mol. Ther, 16, pp.1073~1080 (2008)
- Brown, J. L., "Mitochondrial degeneration precedes the development of muscle atrophy in progression of cancer cachexia in tumour-bearing mice", J. Cachexia Sarcopenia Muscle, 8, pp.926~938 (2017)
- Ronn, T., "Age influences DNA methylation and gene expression of COX7A1in human skeletal muscle", Diabetologia, 51, pp.1159~1168 (2008)
- Fielding, R. A., "Sarcopenia: an undiagnosed condition in older adults. Current consensus definition: prevalence, etiology, and consequences. International working group on sarcopenia", J. Am. Med Dir. Assoc, 12, pp.249~256 (2011)
- Prola, A., "Cardiolipin content controls mitochondrial coupling and energetic efficiency in muscle", Sci. Adv, 7, pp.eabd6322~ (2021)
- Fajardo, V. A., "Cardiolipin content, linoleic acid composition, and tafazzin expression in response to skeletal muscle overload and unload stimuli", Sci. Rep, 7, pp.2060~ (2017)
- Lee, R. G., "Deleterious variants in CRLS1 lead to cardiolipin deficiency and cause an autosomal recessive multi-system mitochondrial disease", Hum. Mol. Genet, 31, pp.3597~3612 (2022)
