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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Torres, Michelle Gu, Haiwei Tsang, Mark Reyes, Nicholas L. Hirenallur-s, Dinesh K. Liggitt, H. Denny Djukovic, Danijel Iritani, Brian M. Margineantu, Daciana Hockenbery, David M. Chan, Jacky Raftery, Daniel Banks, Glen B. |
| Description | Author Affiliation: Reyes NL ( The Department of Comparative Medicine, University of Washington, Seattle, WA 98195-7190); Banks GB ( Department of Neurology, University of Washington, Seattle, WA 98195); Tsang M ( The Department of Comparative Medicine, University of Washington, Seattle, WA 98195-7190); Margineantu D ( Clinical Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024); Gu H ( Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, Northwest Metabolomics Research Center, University of Washington, Seattle, WA 98109-8057); Djukovic D ( Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, Northwest Metabolomics Research Center, University of Washington, Seattle, WA 98109-8057); Chan J ( The Department of Comparative Medicine, University of Washington, Seattle, WA 98195-7190); Torres M ( The Department of Comparative Medicine, University of Washington, Seattle, WA 98195-7190); Liggitt HD ( The Department of Comparative Medicine, University of Washington, Seattle, WA 98195-7190); Hirenallur-S DK ( The Department of Comparative Medicine, University of Washington, Seattle, WA 98195-7190); Hockenbery DM ( Clinical Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024); Raftery D ( Department of Anesthesiology and Pain Medicine, Mitochondria and Metabolism Center, Northwest Metabolomics Research Center, University of Washington, Seattle, WA 98109-8057); Iritani BM ( The Department of Comparative Medicine, University of Washington, Seattle, WA 98195-7190); |
| Abstract | Mammalian skeletal muscle is broadly characterized by the presence of two distinct categories of muscle fibers called type I 'red' slow twitch and type II 'white' fast twitch, which display marked differences in contraction strength, metabolic strategies, and susceptibility to fatigue. The relative representation of each fiber type can have major influences on susceptibility to obesity, diabetes, and muscular dystrophies. However, the molecular factors controlling fiber type specification remain incompletely defined. In this study, we describe the control of fiber type specification and susceptibility to metabolic disease by folliculin interacting protein-1 (Fnip1). Using Fnip1 null mice, we found that loss of Fnip1 increased the representation of type I fibers characterized by increased myoglobin, slow twitch markers [myosin heavy chain 7 (MyH7), succinate dehydrogenase, troponin I 1, troponin C1, troponin T1], capillary density, and mitochondria number. Cultured Fnip1-null muscle fibers had higher oxidative capacity, and isolated Fnip1-null skeletal muscles were more resistant to postcontraction fatigue relative to WT skeletal muscles. Biochemical analyses revealed increased activation of the metabolic sensor AMP kinase (AMPK), and increased expression of the AMPK-target and transcriptional coactivator PGC1 in Fnip1 null skeletal muscle. Genetic disruption of PGC1 rescued normal levels of type I fiber markers MyH7 and myoglobin in Fnip1-null mice. Remarkably, loss of Fnip1 profoundly mitigated muscle damage in a murine model of Duchenne muscular dystrophy. These results indicate that Fnip1 controls skeletal muscle fiber type specification and warrant further study to determine whether inhibition of Fnip1 has therapeutic potential in muscular dystrophy diseases. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 2 |
| Volume Number | 112 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2015-01-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Carrier Proteins Physiology Muscle Fibers, Fast-Twitch Pathology Muscle Fibers, Slow-Twitch Muscular Dystrophy, Duchenne Physiopathology AMP-Activated Protein Kinases Metabolism Animals Genetics Disease Models, Animal Mice Mice, Inbred Mdx Mice, Knockout Mitochondria, Muscle Multiprotein Complexes Muscle Contraction Muscle Fatigue Myoglobin Myosin Heavy Chains TOR Serine-Threonine Kinases Transcription Factors Deficiency Research Support, N.I.H., Extramural Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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