Effect of resveratrol and caloric restriction on mitochondrial regulation and apoptotic susceptibility in aged rat skeletal muscle

Abstract

Sarcopenia is an age‐related loss in muscle mass partially attributable to mitochondrial‐mediated apoptosis. Caloric restriction (CR) and resveratrol (RSV) treatment in rodents induces beneficial mitochondrial alterations which may serve to suppress sarcopenia. Doxorubicin (DOX) is a chemotherapeutic agent that induces cell death via mitochondria. We investigated whether RSV (50 mg/kg/day; 6 weeks) and/or CR (20% reduced AL; 6 weeks) could 1) induce mitochondrial biogenesis, 2) attenuate apoptotic susceptibility and, 3) reduce DOX‐induced toxicity, in aged rodent muscle. Aged F344xBN rats (26 mo) were split into 8 groups (n=4): ad libitum (AL), CR, RSV, RSV+CR and injected with DOX (20 mg/kg; IP) or saline prior (24h) to sacrifice. Mitochondrial content/regulation (cyto c, COX activity, PGC‐1á, SIRT3) and apoptotic susceptibility (Bax:Bcl‐2) were assessed in hindlimb muscle. Surprisingly, mitochondrial indices were unaffected by CR, RSV or CR+RSV, and DOX did not affect any group. CR+RSV reduced (50%) the Bax:Bcl2 ratio compared to AL while RSV and CR independently showed trends for reductions. DOX treatment enhanced the Bax:Bcl‐2 in AL while CR, RSV and CR+RSV tended to suppress this DOX‐induction. Our data indicates aged muscle, and DOX‐treatment, increases apoptotic susceptibility and CR+RSV treatment provides modest protection without altering mitochondrial content/regulation.