Muscle-Specific SIRT1 Gain-of-Function Increases Slow-Twitch Fibers and Ameliorates Pathophysiology in a Mouse Model of Duchenne Muscular Dystrophy
SIRT1 is a metabolic sensor and regulator in various mammalian tissues and functions to counteract metabolic and age-related diseases. Here we generated and analyzed mice that express SIRT1 at high levels specifically in skeletal muscle. We show that SIRT1 transgenic muscle exhibits a fiber shift fr...
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| Language: | en_US |
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Public Library of Science
2014
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| Online Access: | http://hdl.handle.net/1721.1/89216 https://orcid.org/0000-0003-4064-2510 https://orcid.org/0000-0003-2762-4844 https://orcid.org/0000-0003-1160-3969 |
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| author | Chalkiadaki, Angeliki Igarashi, Masaki Nasamu, Armiyaw Sebastian Knezevic, Jovana Guarente, Leonard Pershing |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Chalkiadaki, Angeliki Igarashi, Masaki Nasamu, Armiyaw Sebastian Knezevic, Jovana Guarente, Leonard Pershing |
| author_sort | Chalkiadaki, Angeliki |
| collection | MIT |
| description | SIRT1 is a metabolic sensor and regulator in various mammalian tissues and functions to counteract metabolic and age-related diseases. Here we generated and analyzed mice that express SIRT1 at high levels specifically in skeletal muscle. We show that SIRT1 transgenic muscle exhibits a fiber shift from fast-to-slow twitch, increased levels of PGC-1α, markers of oxidative metabolism and mitochondrial biogenesis, and decreased expression of the atrophy gene program. To examine whether increased activity of SIRT1 protects from muscular dystrophy, a muscle degenerative disease, we crossed SIRT1 muscle transgenic mice to mdx mice, a genetic model of Duchenne muscular dystrophy. SIRT1 overexpression in muscle reverses the phenotype of mdx mice, as determined by histology, creatine kinase release into the blood, and endurance in treadmill exercise. In addition, SIRT1 overexpression also results in increased levels of utrophin, a functional analogue of dystrophin, as well as increased expression of PGC-1α targets and neuromuscular junction genes. Based on these findings, we suggest that pharmacological interventions that activate SIRT1 in skeletal muscle might offer a new approach for treating muscle diseases. |
| first_indexed | 2024-09-23T08:28:42Z |
| format | Article |
| id | mit-1721.1/89216 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T08:28:42Z |
| publishDate | 2014 |
| publisher | Public Library of Science |
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| spelling | mit-1721.1/892162022-09-23T12:41:23Z Muscle-Specific SIRT1 Gain-of-Function Increases Slow-Twitch Fibers and Ameliorates Pathophysiology in a Mouse Model of Duchenne Muscular Dystrophy Chalkiadaki, Angeliki Igarashi, Masaki Nasamu, Armiyaw Sebastian Knezevic, Jovana Guarente, Leonard Pershing Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Paul F. Glenn Center for Biology of Aging Research (Massachusetts Institute of Technology) Chalkiadaki, Angeliki Igarashi, Masaki Nasamu, Armiyaw Sebastian Knezevic, Jovana Guarente, Leonard Pershing SIRT1 is a metabolic sensor and regulator in various mammalian tissues and functions to counteract metabolic and age-related diseases. Here we generated and analyzed mice that express SIRT1 at high levels specifically in skeletal muscle. We show that SIRT1 transgenic muscle exhibits a fiber shift from fast-to-slow twitch, increased levels of PGC-1α, markers of oxidative metabolism and mitochondrial biogenesis, and decreased expression of the atrophy gene program. To examine whether increased activity of SIRT1 protects from muscular dystrophy, a muscle degenerative disease, we crossed SIRT1 muscle transgenic mice to mdx mice, a genetic model of Duchenne muscular dystrophy. SIRT1 overexpression in muscle reverses the phenotype of mdx mice, as determined by histology, creatine kinase release into the blood, and endurance in treadmill exercise. In addition, SIRT1 overexpression also results in increased levels of utrophin, a functional analogue of dystrophin, as well as increased expression of PGC-1α targets and neuromuscular junction genes. Based on these findings, we suggest that pharmacological interventions that activate SIRT1 in skeletal muscle might offer a new approach for treating muscle diseases. American Heart Association (Postdoctoral Fellowship) National Institutes of Health (U.S.) Glenn Foundation for Medical Research 2014-09-09T12:54:23Z 2014-09-09T12:54:23Z 2014-07 2013-05 Article http://purl.org/eprint/type/JournalArticle 1553-7404 1553-7390 http://hdl.handle.net/1721.1/89216 Chalkiadaki, Angeliki, Masaki Igarashi, Armiyaw Sebastian Nasamu, Jovana Knezevic, and Leonard Guarente. “Muscle-Specific SIRT1 Gain-of-Function Increases Slow-Twitch Fibers and Ameliorates Pathophysiology in a Mouse Model of Duchenne Muscular Dystrophy.” Edited by Johan Auwerx. PLoS Genet 10, no. 7 (July 17, 2014): e1004490. https://orcid.org/0000-0003-4064-2510 https://orcid.org/0000-0003-2762-4844 https://orcid.org/0000-0003-1160-3969 en_US http://dx.doi.org/10.1371/journal.pgen.1004490 PLoS Genetics Creative Commons Attribution http://creativecommons.org/licenses/by/4.0/ application/pdf Public Library of Science Public Library of Science |
| spellingShingle | Chalkiadaki, Angeliki Igarashi, Masaki Nasamu, Armiyaw Sebastian Knezevic, Jovana Guarente, Leonard Pershing Muscle-Specific SIRT1 Gain-of-Function Increases Slow-Twitch Fibers and Ameliorates Pathophysiology in a Mouse Model of Duchenne Muscular Dystrophy |
| title | Muscle-Specific SIRT1 Gain-of-Function Increases Slow-Twitch Fibers and Ameliorates Pathophysiology in a Mouse Model of Duchenne Muscular Dystrophy |
| title_full | Muscle-Specific SIRT1 Gain-of-Function Increases Slow-Twitch Fibers and Ameliorates Pathophysiology in a Mouse Model of Duchenne Muscular Dystrophy |
| title_fullStr | Muscle-Specific SIRT1 Gain-of-Function Increases Slow-Twitch Fibers and Ameliorates Pathophysiology in a Mouse Model of Duchenne Muscular Dystrophy |
| title_full_unstemmed | Muscle-Specific SIRT1 Gain-of-Function Increases Slow-Twitch Fibers and Ameliorates Pathophysiology in a Mouse Model of Duchenne Muscular Dystrophy |
| title_short | Muscle-Specific SIRT1 Gain-of-Function Increases Slow-Twitch Fibers and Ameliorates Pathophysiology in a Mouse Model of Duchenne Muscular Dystrophy |
| title_sort | muscle specific sirt1 gain of function increases slow twitch fibers and ameliorates pathophysiology in a mouse model of duchenne muscular dystrophy |
| url | http://hdl.handle.net/1721.1/89216 https://orcid.org/0000-0003-4064-2510 https://orcid.org/0000-0003-2762-4844 https://orcid.org/0000-0003-1160-3969 |
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