A Phosphatidylinositol 3-Kinase/Protein Kinase B-independent Activation of Mammalian Target of Rapamycin Signaling Is Sufficient to Induce Skeletal Muscle Hypertrophy

Abstract

It has been widely proposed that signaling by mammalian target of rapamycin (mTOR) is both necessary and sufficient for the induction of skeletal muscle hypertrophy. Evidence for this hypothesis is largely based on studies that used stimuli that activate mTOR via a phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB)-dependent mechanism. However, the stimulation of signaling by PI3K/PKB also can activate several mTOR-independent growth-promoting events; thus, it is not clear whether signaling by mTOR is permissive, or sufficient, for the induction of hypertrophy. Furthermore, the presumed role of mTOR in hypertrophy is derived from studies that used 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/PKBindependent 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 also were 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. In summary, overexpression of Rheb activates mTOR signaling via a PI3K/PKB-independent mechanism and is sufficient to induce skeletal muscle hypertrophy. The hypertrophic effects of Rheb are driven through a rapamycin-sensitive (RS) mechanism, mTOR is the RS element that confers the hypertrophy, and the kinase activity of mTOR is necessary for this event.

Mammalian Target of Rapamycin (mTOR) Signaling Network in Skeletal Myogenesis

“…Rheb most likely exerts this negative regulation through raptor/ mTOR and suppression of IRS1 (64). This is in contrast to a positive role of Rheb in stimulating muscle hypertrophy (73). Although potential off-target effects of RNAi could complicate the interpretation of knockdown outcomes, consistent phenotypic observations from two independent shRNAs for each gene, corroborated by the effect of overexpression of that gene (64), lend confidence to the conclusions drawn from the RNAi studies.…”

Schisandrae fructus enhances myogenic differentiation and inhibits atrophy through protein synthesis in human myotubes

“…25 Several materials, such as leucine and ursolic acid, as well as exercise, have been known to induce skeletal muscle hypertrophy stimulating v-akt murine thymoma viral oncogene homolog (Akt) or mammalian target of rapamycin (mTOR) signaling. [26][27][28][29][30][31][32] Activation of mTOR generates upregulation of phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 (p-4E-BP1) or phosphorylated 70 kDa ribosomal protein S6 kinase (p-P70S6K). Those signals induce hypertrophy by enhancing translation of mRNAs.…”

Muscle-specific 4E-BP1 signaling activation improves metabolic parameters during aging and obesity

“…Skeletal muscle is another candidate for mediating the metabolic protection afforded by reduced mTORC1 signaling, particularly given that activation of the Drosophila equivalent of 4E-BP (d4E-BP) specifically in muscle suppresses age-related tissue degeneration and is sufficient to enhance life span in the fly (12). mTORC1 activity is crucial during muscle development, as modulations that blunt mTORC1 activity cause muscular dystrophy, while enhanced mTORC1 activity is required for muscle hypertrophy and recovery from injury (13)(14)(15)(16)(17). However, sustained activation of mTORC1 in aging animals results in severe myopathy (18,19), suggesting that the effects of mTORC1 activation are tightly regulated and coordinated in skeletal muscle, with proper levels of mTORC1 activity important for both response to injury and long-term tissue function in aging animals.…”