Function of mTOR complex 1 and 2 in skeletal muscle

Growth of an organ during development and during adaptation in the adult can be controlled by alterations either in the number or the size of cells. The two mechanisms are fundamentally different and require distinct regulation. Rapamycin is a cell growth inhibitor used to treat a number of clinical indications including graft rejection and cancer. The molecular target of rapamycin is a Ser/Thr kinase, called TOR in yeast or mTOR in mammals. The evolutionarily conserved TOR pathway controls key aspects of cellular growth and metabolism. Among these are protein synthesis, ribosome biogenesis, nutrient transport and processing, autophagy and mitochondrial function. mTOR assembles into two distinct multiprotein complexes, termed mTORC1 and mTORC2. mTORC1 consists of raptor (regulatory associated protein of mTOR), mLST8 (mammalian lethal with SEC13 protein 8) and mTOR, and is sensitive to rapamycin. mTORC2 consists of rictor (rapamycin insensitive companion of mTOR), mSIN1, mLST8 (mammalian stress activated protein kinase interacting protein 1) and mTOR. As mTORC1 controls cell growth, it has also been implicated in the control of muscle mass. A vast array of genetic and pharmacological studies using rodent models supports this view. In contrast to the role of mTOR in growth, its metabolic readouts in skeletal muscle are poorly characterized. Little is also known of the function of rapamycin-insensitive mTORC2 whose primary readouts are thought to be the organization of the actin cytoskeleton. Recently, mTORC2 has also been proposed to be the essential kinase that phosphorylates PKB/AKT on Ser473.
To circumvent the early embryonic lethality of mice deficient for raptor (i.e. mTORC1) or rictor (i.e. mTORC2), we generated mice with floxed raptor or rictor alleles. Here we describe the phenotype of mice that lack functional mTORC1, mTORC2, or both complexes, specifically in skeletal muscle. We find that deletion of rictor does not cause an overt muscle phenotype. In contrast, raptor-deficient muscles manifest signs of atrophy and become progressively dystrophic. These muscles also display fundamental metabolic changes which involve impaired mitochondrial function. Furthermore, muscles display properties of fast-twitch, glycolytic skeletal muscle, but exhibit structural features and contraction properties indicative of slow-twitch, oxidative muscle fibers. These changes are either due to impaired activation of direct downstream substrates of mTORC1 or due to loss of negative feedback regulation of upstream components of the signaling pathway. Interestingly, this increased upstream signaling causes sustained hyperactivation of PKB/AKT, which is independent of mTORC2 kinase activity. Taken together, we provide unprecedented evidence for a crucial role of mTORC1 in the regulation of fundamental aspects of metabolism in a specific tissue. Furthermore we show that in the absence of negative feedback regulation from mTORC1 downstream components, mTORC2 is dispensable for PKB/AKT activation.