Increased superoxide in vivo accelerates age-associated muscle atrophy through mitochondrial dysfunction and neuromuscular junction degeneration.
Oxidative stress has been implicated in the etiology of age-related muscle loss (sarcopenia). However, the underlying mechanisms by which oxidative stress contributes to sarcopenia have not been thoroughly investigated. To directly examine the role of chronic oxidative stress in vivo, we used a mouse model that lacks the antioxidant enzyme CuZnSOD (Sod1). Sod1(-/-) mice are characterized by high levels of oxidative damage and an acceleration of sarcopenia. In the present study, we demonstrate that muscle atrophy in Sod1(-/-) mice is accompanied by a progressive decline in mitochondrial bioenergetic function and an elevation of mitochondrial generation of reactive oxygen species. In addition, Sod1(-/-) muscle exhibits a more rapid induction of mitochondrial-mediated apoptosis and loss of myonuclei. Furthermore, aged Sod1(-/-) mice show a striking increase in muscle mitochondrial content near the neuromuscular junctions (NMJs). Despite the increase in content, the function of mitochondria is significantly impaired, with increased denervated NMJs and fragmentation of acetylcholine receptors. As a consequence, contractile force in aged Sod1(-/-) muscles is greatly diminished. Collectively, we show that Sod1(-/-) mice display characteristics of normal aging muscle in an accelerated manner and propose that the superoxide-induced NMJ degeneration and mitochondrial dysfunction are potential mechanisms of sarcopenia.
Jang
Youngmok C
YC
Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA.
Lustgarten
Michael S
MS
Liu
Yuhong
Y
Muller
Florian L
FL
Bhattacharya
Arunabh
A
Liang
Hanyu
H
Salmon
Adam B
AB
Brooks
Susan V
SV
Larkin
Lisa
L
Hayworth
Christopher R
CR
Richardson
Arlan
A
Van Remmen
Holly
H
D000367:Age Factors; D000375:Aging / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008931:Mitochondria, Muscle / Q000378:metabolism / Q000473:pathology*; D009119:Muscle Contraction; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D009469:Neuromuscular Junction / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D018384:Oxidative Stress; D011950:Receptors, Cholinergic / Q000378:metabolism; D055948:Sarcopenia / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D013481:Superoxides / Q000378:metabolism*
D011950:Receptors, Cholinergic; D013481:Superoxides; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D053148:Caspase 3