Oxidative stress in skeletal muscle causes severe disturbance of exercise activity without muscle atrophy.
The increase in reactive oxygen species (ROS) levels that occurs during intense exercise has been proposed to be one of the major causes of muscle fatigue. In addition, the accumulation of cellular damage due to ROS is widely regarded to be one of the factors triggering age-related pathological conditions in skeletal muscle. To investigate the pathological significance of oxidative stress in skeletal muscle, we generated skeletal muscle-specific manganese superoxide dismutase-deficient (muscle-Sod2(-/-)) mice. The mutant mice showed severe disturbances in exercise activity, but no atrophic changes in their skeletal muscles. In histological and histochemical analyses, the mutant mice showed centralized nuclei in their muscle fibers and selective loss of enzymatic activity in mitochondrial respiratory chain complexes. In addition, the mutant mice displayed increased oxidative damage and reduced ATP content in their muscle tissue. Furthermore, a single administration of the antioxidant EUK-8 significantly improved exercise activity and increased the cellular ATP level in skeletal muscle. These results imply that the superoxide anions generated in mitochondria play a pivotal role in the progression of exercise intolerance.
Kuwahara
Hirotomo
H
Molecular Gerontology, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0015, Japan.
Horie
Tetsuro
T
Ishikawa
Shin
S
Tsuda
Chizuru
C
Kawakami
Satoru
S
Noda
Yoshihiro
Y
Kaneko
Takao
T
Tahara
Shoichi
S
Tachibana
Toshiaki
T
Okabe
Masataka
M
Melki
Judith
J
Takano
Riya
R
Toda
Toshihiko
T
Morikawa
Daichi
D
Nojiri
Hidetoshi
H
Kurosawa
Hisashi
H
Shirasawa
Takuji
T
Shimizu
Takahiko
T
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D015153:Blotting, Western; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D009133:Muscular Atrophy / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology*; D010805:Physical Conditioning, Animal / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000172:deficiency / Q000235:genetics; D000099156:Superoxide Dismutase 2
D000975:Antioxidants; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2