Exercise-induced AMPK activation is involved in delay of skeletal muscle senescence.

Accumulation of senescent cells leads to aging related phenotypes in various organs. Sarcopenia is a frequently observed aging-related disease, which is associated with the loss of muscle mass and functional disability. Physical activity represents the most critical treatment method for preventing decreased muscle size, mass and strength. However, the underlying mechanism as to how physical activity provides this beneficial effect on muscle function has not yet been fully understood. In particular, one unresolved question about aging is how the boost in catabolism induced by aerobic exercise affects skeletal muscle atrophy and other senescence phenotypes. Here we show that pre-activation of AMPK with the AMPK activator, AICAR can mitigate the diminished cellular viability of skeletal muscle cells induced by doxorubicin, which accelerates senescence through free radical production. Pre-incubation for 3 h with AICAR decreased doxorubicin-induced phosphorylation of AMPK in a differentiated skeletal muscle cell line. Accordingly, cellular viability of skeletal muscle cells was recovered in the cells pre-treated with AICAR then administered doxorubicin as compared to that of doxorubicin-only treatment. In accordance with the results of cellular experiments, we verified that 4 weeks of treadmill exercise decreased the senescence marker, p16 and p21 in 19-month-old mice compared to sedentary mice. In this study, we provide new evidence that prior activation of AMPK can reduce doxorubicin induced cell senescence phenotypes. The evidence in this paper suggest that aerobic exercise-activated catabolism in the skeletal muscle may prevent cellular senescence, partially through the cell cycle regulation.