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Genetically enhancing mitochondrial antioxidant activity improves muscle function in aging.

ABSTRACT: Age-related skeletal muscle dysfunction is a leading cause of morbidity that affects up to half the population aged 80 or greater. Here we tested the effects of increased mitochondrial antioxidant activity on age-dependent skeletal muscle dysfunction using transgenic mice with targeted overexpression of the human catalase gene to mitochondria (MCat mice). Aged MCat mice exhibited improved voluntary exercise, increased skeletal muscle specific force and tetanic Ca(2+) transients, decreased intracellular Ca(2+) leak and increased sarcoplasmic reticulum (SR) Ca(2+) load compared with age-matched wild type (WT) littermates. Furthermore, ryanodine receptor 1 (the sarcoplasmic reticulum Ca(2+) release channel required for skeletal muscle contraction; RyR1) from aged MCat mice was less oxidized, depleted of the channel stabilizing subunit, calstabin1, and displayed increased single channel open probability (Po). Overall, these data indicate a direct role for mitochondrial free radicals in promoting the pathological intracellular Ca(2+) leak that underlies age-dependent loss of skeletal muscle function. This study harbors implications for the development of novel therapeutic strategies, including mitochondria-targeted antioxidants for treatment of mitochondrial myopathies and other healthspan-limiting disorders.

SUBMITTER: Umanskaya A

PROVIDER: S-EPMC4210348 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Genetically enhancing mitochondrial antioxidant activity improves muscle function in aging.

Umanskaya Alisa A Santulli Gaetano G Xie Wenjun W Andersson Daniel C DC Reiken Steven R SR Marks Andrew R AR

Proceedings of the National Academy of Sciences of the United States of America 20141006 42

Age-related skeletal muscle dysfunction is a leading cause of morbidity that affects up to half the population aged 80 or greater. Here we tested the effects of increased mitochondrial antioxidant activity on age-dependent skeletal muscle dysfunction using transgenic mice with targeted overexpression of the human catalase gene to mitochondria (MCat mice). Aged MCat mice exhibited improved voluntary exercise, increased skeletal muscle specific force and tetanic Ca(2+) transients, decreased intrac ...[more]

PMID: 25288763

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Genetically enhancing mitochondrial antioxidant activity improves muscle function in aging.

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Genetically enhancing mitochondrial antioxidant activity improves muscle function in aging.

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