Background:Doxorubicin (DOX), a widely used anti-cancer drug, induces skeletal muscle atrophy. We recently reported that aging-related skeletal muscle atrophy is attenuated by treatment of mice with resveratrol (RSV), an activator of an NAD⁺-dependent protein deacetylase SIRT1. In this study, we examined the effects of RSV on DOX-induced skeletal muscle atrophy.
Methods and Results:Male mice were randomly grouped into three: vehicle, DOX, and RSV+DOX groups. In the DOX and RSV+DOX groups, mice were treated with DOX (5 mg/kg, IP) 4 times every 7 days. In the RSV+DOX group, mice were fed RSV-containing diet (0.4 g/kg) for 6 weeks starting 1 week before first DOX treatment. Body weight was measured every 7 days. Tibialis anterior muscles (TA) and gastrocnemius muscles (GAS) were obtained at 1 week after the last DOX administration. Body weight was gradually decreased in the DOX group compared to the vehicle group but was partially maintained in the RSV+DOX group. TA and GAS weights were reduced in the DOX group, indicating skeletal muscle atrophy. RSV treatment blocked the reductions in TA and GAS weights induced by DOX. In GAS, Western blot analysis showed an increase in acetylated lysine levels in the DOX group compared to the vehicle group. This DOX-induced increase in lysine acetylation was suppressed by RSV, suggesting that a decrease in SIRT1 activity by DOX was recovered by RSV.
Conclusion:These results suggest that activation of SIRT1 by RSV prevented skeletal muscle atrophy induced by DOX.