{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T22:26:28Z","timestamp":1790720788208,"version":"4.1.0"},"reference-count":40,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2022,6,28]],"date-time":"2022-06-28T00:00:00Z","timestamp":1656374400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["PL895\/1\u20101"],"award-info":[{"award-number":["PL895\/1\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SFB 1218\/TP B07"],"award-info":[{"award-number":["SFB 1218\/TP B07"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001655","name":"Deutscher Akademischer Austauschdienst","doi-asserted-by":"publisher","award":["91524219"],"award-info":[{"award-number":["91524219"]}],"id":[{"id":"10.13039\/501100001655","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2022,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Mitochondrial dysfunction caused by mitochondrial (mtDNA) deletions have been associated with skeletal muscle atrophy and myofibre loss. However, whether such defects occurring in myofibres cause sarcopenia is unclear. Also, the contribution of mtDNA alterations in muscle stem cells (MuSCs) to sarcopenia remains to be investigated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We expressed a dominant\u2010negative variant of the mitochondrial helicase, which induces mtDNA alterations, specifically in differentiated myofibres (K320E<jats:sup>skm<\/jats:sup> mice) and MuSCs (K320E<jats:sup>msc<\/jats:sup> mice), respectively, and investigated their impact on muscle structure and function by immunohistochemistry, analysis of mtDNA and respiratory chain content, muscle transcriptome and functional tests.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>K320E<jats:sup>skm<\/jats:sup> mice at 24\u00a0months of age had higher levels of mtDNA deletions compared with controls in soleus (SOL, 0.07673% vs. 0.00015%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.0167), extensor digitorum longus (EDL, 0.0649 vs. 0.000925, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.0015) and gastrocnemius (GAS, 0.09353 vs. 0.000425, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.0004). K320E<jats:sup>skm<\/jats:sup> mice revealed a progressive increase in the proportion of cytochrome c oxidase deficient (COX<jats:sup>\u2212<\/jats:sup>) fibres in skeletal muscle cross sections, reaching a maximum of 3.03%, 4.36%, 13.58%, and 17.08% in EDL, SOL, tibialis anterior (TA) and GAS, respectively. However, mice did not show accelerated loss of muscle mass, muscle strength or physical performance. Histological analyses revealed ragged red fibres but also stimulated regeneration, indicating activation of MuSCs. RNAseq demonstrated enhanced expression of genes associated with protein synthesis, but also degradation, as well as muscle fibre differentiation and cell proliferation. In contrast, 7\u00a0days after destruction by cardiotoxin, regenerating TA of K320E<jats:sup>msc<\/jats:sup> mice showed 30% of COX<jats:sup>\u2212<\/jats:sup> fibres. Notably, regenerated muscle showed dystrophic changes, increased fibrosis (2.5% vs. 1.6%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.0003), increased abundance of fat cells (2.76% vs. 0.23%, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.0144) and reduced muscle mass (regenerated TA: 40.0\u00a0mg vs. 60.2\u00a0mg, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.0171). In contrast to muscles from K320E<jats:sup>skm<\/jats:sup> mice, freshly isolated MuSCs from aged K320E<jats:sup>msc<\/jats:sup> mice were completely devoid of mtDNA alterations. However, after passaging, mtDNA copy number as well as respiratory chain subunits and p62 levels gradually decreased.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Taken together, accumulation of large\u2010scale mtDNA alterations in myofibres alone is not sufficient to cause sarcopenia. Expression of K320E\u2010Twinkle is tolerated in quiescent MuSCs, but progressively leads to mtDNA and respiratory chain depletion upon activation, <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic>, possibly caused by an increased mitochondrial removal. Altogether, our results suggest that the accumulation of mtDNA alterations in myofibres activates regeneration during aging, which leads to sarcopenia if such alterations have expanded in MuSCs as well.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.13026","type":"journal-article","created":{"date-parts":[[2022,6,29]],"date-time":"2022-06-29T04:11:02Z","timestamp":1656475862000},"page":"2132-2145","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Combined fibre atrophy and decreased muscle regeneration capacity driven by mitochondrial DNA alterations underlie the development of sarcopenia"],"prefix":"10.1002","volume":"13","author":[{"given":"Sammy","family":"Kimoloi","sequence":"first","affiliation":[{"name":"Institute of Vegetative Physiology University of Cologne, Faculty of Medicine and University Clinics  K\u00f6ln Germany"},{"name":"Department of Medical Laboratory Sciences Masinde Muliro University of Science 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