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The formation of multi-nucleated muscle fibers from progenitors requires the fine-tuned and coordinated regulation of proliferation, differentiation and fusion, both during development and after injury in the adult. Although some of the key factors that are involved in the different steps are well known, how intracellular signals are coordinated and integrated is largely unknown. Here, we investigated the role of the cell-growth regulator mTOR by eliminating essential components of the mTOR complexes 1 (mTORC1) and 2 (mTORC2) in mouse muscle progenitors. We show that inactivation of mTORC1, but not mTORC2, in developing muscle causes perinatal death. In the adult, mTORC1 deficiency in muscle stem cells greatly impinges on injury-induced muscle regeneration. These phenotypes are because of defects in the proliferation and fusion capacity of the targeted muscle progenitors. However, mTORC1-deficient muscle progenitors partially retain their myogenic function. Hence, our results show that mTORC1 and not mTORC2 is an important regulator of embryonic and adult myogenesis, and they point to alternative pathways that partially compensate for the loss of mTORC1.This article has an associated 'The people behind the papers' interview.

Long non-coding RNAs (lncRNAs) belong to the ever-increasing number of transcripts that are thought not to encode proteins. A recent study has now identified a small polypeptide encoded by the lncRNA LINC00961 that inhibits amino acid-induced mTORC1 activation in skeletal muscle.

Myotonic dystrophy type I (DM1) is a disabling multisystemic disease that predominantly affects skeletal muscle. It is caused by expanded CTG repeats in the 3'-UTR of the dystrophia myotonica protein kinase (DMPK) gene. RNA hairpins formed by elongated DMPK transcripts sequester RNA-binding proteins, leading to mis-splicing of numerous pre-mRNAs. Here, we have investigated whether DM1-associated muscle pathology is related to deregulation of central metabolic pathways, which may identify potential therapeutic targets for the disease. In a well-characterized mouse model for DM1 (HSALR mice), activation of AMPK signaling in muscle was impaired under starved conditions, while mTORC1 signaling remained active. In parallel, autophagic flux was perturbed in HSALR muscle and in cultured human DM1 myotubes. Pharmacological approaches targeting AMPK/mTORC1 signaling greatly ameliorated muscle function in HSALR mice. AICAR, an AMPK activator, led to a strong reduction of myotonia, which was accompanied by partial correction of misregulated alternative splicing. Rapamycin, an mTORC1 inhibitor, improved muscle relaxation and increased muscle force in HSALR mice without affecting splicing. These findings highlight the involvement of AMPK/mTORC1 deregulation in DM1 muscle pathophysiology and may open potential avenues for the treatment of this disease.

SummaryAutophagy is a catabolic process that ensures homeostatic cell clearance and is deregulated in a growing number of myopathological conditions. Although FoxO3 was shown to promote the expression of autophagy-related genes in skeletal muscle, the mechanisms triggering autophagy are unclear. We show that TSC1-deficient mice (TSCmKO), characterized by sustained activation of mTORC1, develop a late-onset myopathy related to impaired autophagy. In young TSCmKO mice, constitutive and starvation-induced autophagy is blocked at the induction steps via mTORC1-mediated inhibition of Ulk1, despite FoxO3 activation. Rapamycin is sufficient to restore autophagy in TSCmKO mice and improves the muscle phenotype of old mutant mice. Inversely, abrogation of mTORC1 signaling by depletion of raptor induces autophagy regardless of FoxO inhibition. Thus, mTORC1 is the dominant regulator of autophagy induction in skeletal muscle and ensures a tight coordination of metabolic pathways. These findings may open interesting avenues for therapeutic strategies directed toward autophagy-related muscle diseases.