Muscle-Specific SIRT1 Gain-of-Function Increases Slow-Twitch Fibers and Ameliorates Pathophysiology in a Mouse Model of Duchenne Muscular Dystrophy
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Chalkiadaki-2014-Muscle-Specific SIRT.pdf
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Author(s)
Chalkiadaki, Angeliki
Igarashi, Masaki
Nasamu, Armiyaw Sebastian
Knezevic, Jovana
Guarente, Leonard Pershing
Date Issued
July 2014
Journal
PLoS Genetics
Publisher
Public Library of Science
Citation
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.
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Final published version
Abstract
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.
MIT Department
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)
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DOI of Published Version
https://doi.org/10.1371/journal.pgen.1004490
