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Oxidative stress induced mitochondrial dysfunction leads to age related loss of muscle mass via myonuclear apoptosis and proteolysis
Author(s) -
Jang Young Charles,
Muller Florian L.,
Hayworth Chris,
Liu Yuhong,
Richardson Arlan,
Van Remmen Holly
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.758.33
Subject(s) - sarcopenia , oxidative stress , apoptosis , skeletal muscle , proteolysis , mitochondrion , calpain , myocyte , chemistry , sod1 , caspase 3 , microbiology and biotechnology , fragmentation (computing) , caspase , endocrinology , medicine , programmed cell death , oxidative phosphorylation , cytochrome c , biology , biochemistry , superoxide dismutase , enzyme , ecology
Aging is accompanied by the loss of skeletal muscle mass and function (sarcopenia). Mice lacking the antioxidant enzyme CuZnSOD ( Sod1 −/− ) exhibit high oxidative stress in skeletal muscle and an accelerated sarcopenia. Mitochondria isolated from Sod1 −/− muscle generates significantly elevated levels of H 2 O 2 and show a decline in mitochondrial function. We hypothesized that the accelerated sarcopenia in Sod1 −/− mice, is due to increased mitochondrial oxidative damage which results in apoptotic deletion of myonuclei and proteolysis. Sod1 −/− muscle mitochondria show increased levels of cytochrome c and apoptosis inducing factor (AIF) release. These data are supported by an increase in downstream events; caspase‐9, caspase‐3 activity, DNA fragmentation, and cell‐free apoptosis. However, the myonuclear domain (myofiber volume/myonuclei) is not affected by myonuclear apoptosis. Therefore, it is likely that muscle cells respond to apoptosis by reducing its size via proteolysis. Indeed, cysteine protease, calpain and the 26S proteasome activity is increased by approximately 15~20% along with increased overall ubiquitinylation in Sod1 −/− skeletal muscle. Overall, our data support the hypothesis that oxidative stress induced mitochondrial dysfunction leads to myonuclear apoptosis and proteolysis. This could be a possible underlying mechanism of age related muscle loss and function.