Autophagy is a vesicular trafficking pathway that regulates the degradation of aggregated proteins and damaged organelles. Initiation of autophagy requires several multiprotein signaling complexes, such as the ULK1 kinase complex and the Vps34 lipid kinase complex, which generates phosphatidylinositol 3-phosphate [PtdIns(3)P] on the forming autophagosomal membrane. Alterations in autophagy have been reported for various diseases, including myopathies. Here we show that skeletal muscle autophagy is compromised in mice deficient in the X-linked myotubular myopathy (XLMTM)-associated PtdIns(3)P phosphatase myotubularin (MTM1). Mtm1-deficient muscle displays several cellular abnormalities, including a profound increase in ubiquitin aggregates and abnormal mitochondria. Further, we show that Mtm1 deficiency is accompanied by activation of mTORC1 signaling, which persists even following starvation. In vivo pharmacological inhibition of mTOR is sufficient to normalize aberrant autophagy and improve muscle phenotypes in Mtm1 null mice. These results suggest that aberrant mTORC1 signaling and impaired autophagy are consequences of the loss of Mtm1 and may play a primary role in disease pathogenesis.T he autophagy-lysosomal pathway regulates the degradation of bulk cytosol, protein aggregates, and mitochondria. Nutrient limitation represents one of the major ways in which autophagy is activated, and in this context, the recycling of cellular components provides the cell with a source of ATP and amino acids to maintain normal homeostatic processes (1). Tissue-specific deletion of essential autophagy genes (ATG) such as Atg5 or Atg7 has revealed that autophagy plays a cytoprotective role by degrading potentially toxic aggregated proteins and damaged organelles (2-9). The regulation of autophagy is complex but can be categorized into three major phases: initiation, maturation and, degradation (10). The ULK1-Atg13-FIP200 complex plays an essential role in certain nucleating events during initiation (11). This complex is regulated by mTOR (12-14), which itself assembles into two multiprotein complexes termed mTORC1 and mTORC2 (15). The two complexes can be distinguished on the basis of unique components, namely, Raptor and Rictor, which associate with mTORC1 and mTORC2, respectively (16-18). mTORC1 suppresses autophagy and in parallel promotes cell growth via the activation of eIF4E and ribosomal S6 protein kinase (S6K) (15). Inhibition of mTORC1 by nutrient deprivation or pharmacological inhibitors such as rapamycin results in the activation of ULK1 and autophagy (11). In addition to ULK1, the class III phosphatidylinositol 3-kinase Vps34 is required for the formation of autophagosomes during pathway initiation. It is believed that following activation of the ULK1 complex, ATG14L recruits Vps34 to the surface of the endoplasmic reticulum, where it catalyzes the production of phosphatidylinositol 3-phosphate [PtdIns(3)P] (19-21). The exact role of PtdIns(3)P in autophagy is unclear, but studies suggest that PtdIns(3)P recruits...

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