Rapamycin prevents the post‐exercise increase in protein synthesis and alters cell signaling in human skeletal muscle

Abstract

Resistance exercise stimulates mTOR signaling and muscle protein synthesis (MPS) during post‐exercise recovery in humans. Rapamycin is a specific inhibitor of mTOR and is often used to inhibit protein synthesis in cell models and rodent skeletal muscle in vivo. We hypothesized that the administration of rapamycin to human subjects prior to a bout of resistance exercise would prevent the increase in MPS during early post‐exercise recovery. We studied young men that ingested rapamycin (12mg) 2 hr prior to exercise (Rapamycin; N=7) and a Control group that did not receive rapamycin (N=8). Rapamycin and Control subjects performed a bout of heavy resistance exercise and muscle biopsies were obtained at 1 and 2 hours post‐exercise. Stable isotope and immunoblotting techniques were used to determine MPS and phosphorylation of proteins involved in the regulation of MPS. We found that MPS increased during post‐exercise recovery in the Control group (P<0.05) but was unchanged in the Rapamycin group (P>0.05). In addition, phosphorylation of mTOR (Ser2448), S6K1 (Thr389) and S6 (Ser240/244 and 235/236) were partially inhibited and S6K1 (Thr421/Ser424), eEF2 (Thr56) and ERK1/2 (Thr202/Tyr204) and MNK1 (Thr197/202) were completely blocked during post‐exercise recovery in the Rapamycin group. Raptor association with mTORC1 also tended to be higher in the Control group (as compared to the Rapamycin group) at 2 hours post‐exercise (P=0.06). We conclude that the increase in MPS following an acute bout of resistance exercise appears to be rapamycin dependent indicating that mTOR signaling is playing an important role in regulating the post‐exercise protein anabolic response.Supported by NIH/NIAMS grant # RO1 AR049877 and P30AG024832.