Modulation of mTOR signaling as a strategy for the treatment of Pompe disease
Abstract 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...
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| Format: | Article |
| Language: | English |
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Springer Nature
2017-01-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201606547 |
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| author | Jeong‐A Lim Lishu Li Orian S Shirihai Kyle M Trudeau Rosa Puertollano Nina Raben |
| author_facet | Jeong‐A Lim Lishu Li Orian S Shirihai Kyle M Trudeau Rosa Puertollano Nina Raben |
| author_sort | Jeong‐A Lim |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-2a77204e7b804f809d25558a01eea95f |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2017-01-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-2a77204e7b804f809d25558a01eea95f2025-08-20T03:46:11ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842017-01-019335337010.15252/emmm.201606547Modulation of mTOR signaling as a strategy for the treatment of Pompe diseaseJeong‐A Lim0Lishu Li1Orian S Shirihai2Kyle M Trudeau3Rosa Puertollano4Nina Raben5Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of HealthLaboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of HealthDepartment of Medicine, Obesity and Nutrition Section, Evans Biomedical Research Center, Boston University School of MedicineDepartment of Medicine, Obesity and Nutrition Section, Evans Biomedical Research Center, Boston University School of MedicineCell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of HealthLaboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of HealthAbstract 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.https://doi.org/10.15252/emmm.201606547autophagylysosomal storage disordersmTORmyopathyPompe disease |
| spellingShingle | Jeong‐A Lim Lishu Li Orian S Shirihai Kyle M Trudeau Rosa Puertollano Nina Raben Modulation of mTOR signaling as a strategy for the treatment of Pompe disease EMBO Molecular Medicine autophagy lysosomal storage disorders mTOR myopathy Pompe disease |
| title | Modulation of mTOR signaling as a strategy for the treatment of Pompe disease |
| title_full | Modulation of mTOR signaling as a strategy for the treatment of Pompe disease |
| title_fullStr | Modulation of mTOR signaling as a strategy for the treatment of Pompe disease |
| title_full_unstemmed | Modulation of mTOR signaling as a strategy for the treatment of Pompe disease |
| title_short | Modulation of mTOR signaling as a strategy for the treatment of Pompe disease |
| title_sort | modulation of mtor signaling as a strategy for the treatment of pompe disease |
| topic | autophagy lysosomal storage disorders mTOR myopathy Pompe disease |
| url | https://doi.org/10.15252/emmm.201606547 |
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