Rapamycin does not compromise physical performance or muscle hypertrophy after PoWeR while intermittent rapamycin alleviates glucose disruptions by frequent rapamycin.

An increasing number of physically active adults are taking the mTOR inhibitor rapamycin off label with the goal of extending healthspan. However, frequent rapamycin dosing disrupts metabolic health during sedentary conditions and abates the anabolic response to exercise. Intermittent once weekly rapamycin dosing minimizes many negative metabolic side effects of frequent rapamycin in sedentary mice. However, it remains unknown how different rapamycin dosing schedules impact metabolic, physical, and skeletal muscle adaptations to voluntary exercise training. Therefore, we tested the hypothesis that intermittent rapamycin (2mg/kg; 1x/week) would avoid detrimental effects on adaptations to 8 weeks of progressive weighted wheel running (PoWeR) in adult female mice (5-month-old) by evading the sustained inhibitory effects on mTOR signaling by more frequent dosing schedules (2mg/kg; 3x/week). Frequent but not intermittent rapamycin suppressed skeletal muscle mTORC1 signaling in PoWeR trained mice. PoWeR improved maximal exercise capacity, absolute grip strength, and myofiber hypertrophy with no differences between vehicle or rapamycin treated mice. Conversely, frequent and intermittent rapamycin treated mice had impaired glucose tolerance and insulin sensitivity compared to vehicle treated mice after PoWeR; however, intermittent rapamycin reduced the impact on glucose intolerance versus frequent rapamycin. Collectively, these data in adult female mice suggest that 1) rapamycin is largely compatible with the physical and skeletal muscle benefits of PoWeR and 2) the detrimental effects of rapamycin on body composition and glucose metabolism in the context of voluntary exercise may be reduced by intermittent dosing.