A PI3K/PKB-Independent Activation of mTOR Signaling is Sufficient to Induce Skeletal Muscle Hypertrophy

It has been widely proposed that signaling by mTOR is both necessary and sufficient for the induction of skeletal muscle hypertrophy. Evidence for this hypothesis is largely based on studies which employed stimuli that activate mTOR via a PI3K/PKB-dependent mechanism. However, the stimulation of signaling by PI3K/PKB can also activate several mTOR-independent growth promoting events, and thus, it is not clear if signaling by mTOR is permissive, or sufficient, for the induction of hypertrophy. Furthermore, the presumed role of mTOR in hypertrophy is derived from studies which utilized rapamycin to inhibit mTOR, yet, there is very little direct evidence that mTOR is the rapamycin-sensitive element that confers the hypertrophic response. In this study we determined that, in skeletal muscle, overexpression of Rheb stimulates a PI3K/PKB-independent activation of mTOR signaling and this is sufficient for the induction of a rapamycin-sensitive hypertrophic response. Transgenic mice with muscle specific expression of various mTOR mutants were also used to demonstrate that mTOR is the rapamycin-sensitive element that conferred the hypertrophic response and that the kinase activity of mTOR is necessary for this event. Combined, these results provide direct genetic evidence that a PI3K/PKB-independent activation of mTOR signaling is sufficient to induce hypertrophy.