Present Address: Department of Stem Cell & Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 02138, USA.
Dietary restriction attenuates age-associated muscle atrophy by lowering oxidative stress in mice even in complete absence of CuZnSOD
Version of Record online: 2 AUG 2012
© 2012 The Authors. Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland
Volume 11, Issue 5, pages 770–782, October 2012
How to Cite
Jang, Y. C., Liu, Y., Hayworth, C. R., Bhattacharya, A., Lustgarten, M. S., Muller, F. L., Chaudhuri, A., Qi, W., Li, Y., Huang, J.-Y., Verdin, E., Richardson, A. and Van Remmen, H. (2012), Dietary restriction attenuates age-associated muscle atrophy by lowering oxidative stress in mice even in complete absence of CuZnSOD. Aging Cell, 11: 770–782. doi: 10.1111/j.1474-9726.2012.00843.x
- Issue online: 16 SEP 2012
- Version of Record online: 2 AUG 2012
- Accepted manuscript online: 5 JUN 2012 09:50AM EST
- Accepted for publication 27 May 2012
- calorie restriction;
- oxidative stress;
- reactive oxygen species;
- skeletal muscle
Age-related loss of muscle mass and function, sarcopenia, has a major impact on the quality of life in the elderly. Among the proposed causes of sarcopenia are mitochondrial dysfunction and accumulated oxidative damage during aging. Dietary restriction (DR), a robust dietary intervention that extends lifespan and modulates age-related pathology in a variety of species, has been shown to protect from sarcopenia in rodents. Although the mechanism(s) by which DR modulates aging are still not defined, one potential mechanism is through modulation of oxidative stress and mitochondrial dysfunction. To directly test the protective effect of DR against oxidative stress–induced muscle atrophy in vivo, we subjected mice lacking a key antioxidant enzyme, CuZnSOD (Sod1) to DR (60% of ad libitum fed diet). We have previously shown that the Sod1−/− mice exhibit an acceleration of sarcopenia associated with high oxidative stress, mitochondrial dysfunction, and severe neuromuscular innervation defects. Despite the dramatic atrophy phenotype in the Sod1−/− mice, DR led to a reversal or attenuation of reduced muscle function, loss of innervation, and muscle atrophy in these mice. DR improves mitochondrial function as evidenced by enhanced Ca2+ regulation and reduction of mitochondrial reactive oxygen species (ROS). Furthermore, we show upregulation of SIRT3 and MnSOD in DR animals, consistent with reduced mitochondrial oxidative stress and reduced oxidative damage in muscle tissue measured as F2-isoprostanes. Collectively, our results demonstrate that DR is a powerful mediator of mitochondrial function, mitochondrial ROS production, and oxidative damage, providing a solid protection against oxidative stress–induced neuromuscular defects and muscle atrophy in vivo even under conditions of high oxidative stress.