| Calsarcin-2 deficiency increases exercise capacity in mice through calcineurin/NFAT activation. | |
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MedLine Citation:
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PMID: 18846255 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The composition of skeletal muscle, in terms of the relative number of slow- and fast-twitch fibers, is tightly regulated to enable an organism to respond and adapt to changing physical demands. The phosphatase calcineurin and its downstream targets, transcription factors of the nuclear factor of activated T cells (NFAT) family, play a critical role in this process by promoting the formation of slow-twitch, oxidative fibers. Calcineurin binds to calsarcins, a family of striated muscle-specific proteins of the sarcomeric Z-disc. We show here that mice deficient in calsarcin-2, which is expressed exclusively by fast-twitch muscle and encoded by the myozenin 1 (Myoz1) gene, have substantially reduced body weight and fast-twitch muscle mass in the absence of an overt myopathic phenotype. Additionally, Myoz1 KO mice displayed markedly improved performance and enhanced running distances in exercise studies. Analysis of fiber type composition of calsarcin-2-deficient skeletal muscles showed a switch toward slow-twitch, oxidative fibers. Reporter assays in cultured myoblasts indicated an inhibitory role for calsarcin-2 on calcineurin, and Myoz1 KO mice exhibited both an excess of NFAT activity and an increase in expression of regulator of calcineurin 1-4 (RCAN1-4), indicating enhanced calcineurin signaling in vivo. Taken together, these results suggest that calsarcin-2 modulates exercise performance in vivo through regulation of calcineurin/NFAT activity and subsequent alteration of the fiber type composition of skeletal muscle. |
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Authors:
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Norbert Frey; Derk Frank; Stefanie Lippl; Christian Kuhn; Harald Kögler; Tomasa Barrientos; Claudia Rohr; Rainer Will; Oliver J Müller; Hartmut Weiler; Rhonda Bassel-Duby; Hugo A Katus; Eric N Olson |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2008-10-09 |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 118 ISSN: 0021-9738 ISO Abbreviation: J. Clin. Invest. Publication Date: 2008 Nov |
Date Detail:
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Created Date: 2008-11-04 Completed Date: 2009-01-12 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: United States |
Other Details:
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Languages: eng Pagination: 3598-608 Citation Subset: AIM; IM |
Affiliation:
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Department of Internal Medicine III, University of Heidelberg, Heidelberg, Germany. norbert.frey@med.uni-heidelberg.de |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Calcineurin / metabolism* Carrier Proteins / genetics, ultrastructure Cell Line Genes, Reporter Mice Mice, Knockout Models, Biological Muscle Fibers, Slow-Twitch / physiology Muscle Proteins / deficiency*, genetics, ultrastructure Myoblasts / cytology, metabolism NFATC Transcription Factors / metabolism* Physical Conditioning, Animal* |
| Chemical | |
Reg. No./Substance:
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0/Carrier Proteins; 0/Muscle Proteins; 0/NFATC Transcription Factors; 0/calsarcin-2 protein, mouse; EC 3.1.3.16/Calcineurin |
| Comments/Corrections | |
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