Journal
EMBO MOLECULAR MEDICINE
Volume 9, Issue 3, Pages 353-370Publisher
WILEY
DOI: 10.15252/emmm.201606547
Keywords
autophagy; lysosomal storage disorders; mTOR; myopathy; Pompe disease
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Funding
- National Institute of Arthritis and Musculoskeletal and Skin diseases of the National Institutes of Health
- CRADA
- Acid Maltase Deficiency Association
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Mechanistic target of rapamycin (mTOR) coordinates biosynthetic and catabolic processes in response to multiple extracellular and intracellular signals including growth factors and nutrients. This serine/threonine kinase has long been known as a critical regulator of muscle mass. The recent finding that the decision regarding its activation/inactivation takes place at the lysosome undeniably brings mTOR into the field of lysosomal storage diseases. In this study, we have examined the involvement of the mTOR pathway in the pathophysiology of a severe muscle wasting condition, Pompe disease, caused by excessive accumulation of lysosomal glycogen. Here, we report the dysregulation of mTOR signaling in the diseased muscle cells, and we focus on potential sites for therapeutic intervention. Reactivation of mTOR in the whole muscle of Pompe mice by TSC knockdown resulted in the reversal of atrophy and a striking removal of autophagic buildup. Of particular interest, we found that the aberrant mTOR signaling can be reversed by arginine. This finding can be translated into the clinic and may become a paradigm for targeted therapy in lysosomal, metabolic, and neuromuscular diseases.
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