Duchenne muscular dystrophy (DMD), characterized by progressive muscle weakness and early death, is caused by diverse mutations in the dystrophin gene and subsequent perturbations in the fundamental cellular processes such as autophagy. Although the link between dystrophin and the regulation of autophagy has been recognized, the molecular mechanisms mediating the autophagy defect in DMD muscle remain ill-defined. Previous studies have suggested that hyperactivation of Akt and its downstream target mammalian target of rapamycin complex 1 (mTORC1), a major autophagy suppressor, primarily contributes to the autophagy-dependent pathogenesis of DMD. In the present study, we also observed activation of mTORC1 signaling and impaired autophagy in the skeletal muscle of mdx mice, a model of DMD. Surprisingly, however, we did not obtain any evidence for an increase in Akt activity in the same muscle, measured by the phosphorylation of Akt and its direct substrates. Instead, we found that loss of dystrophin leads to a unique increase in the expression of leucyl-tRNA synthetase (LRS), another critical activator of mTORC1 that acts independently of Akt through interaction with RagD. Administration of a specific LRS-RagD interaction inhibitor BC-LI-0186 not only suppressed mTORC1 signaling but also re-activated autophagy in the mdx muscle. More importantly, BC-LI-0186 significantly restored muscle strength in mdx mice, and an autophagy inhibitor Chloroquine fully reversed this rescue effect. Combined, these results strongly suggest that LRS, but not Akt, mediates dystrophin deficiency-induced mTORC1 activation, autophagy impairment, and muscle weakness and highlight LRS as a potential therapeutic target for DMD.