Fiber-type Switching, Exercise Intolerance, and Myopathy in PGC-1α Muscle-specific Knock-out Animals

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Citation Handschin, Christoph, Sherry Chin, Ping Li, Fenfen Liu, Eleftheria Maratos-Flier, Nathan K. LeBrasseur, Zhen Yan, and Bruce M. Spiegelman. 2007. “Skeletal Muscle Fiber-Type Switching, Exercise Intolerance, and Myopathy in PGC-1α Muscle-Specific Knock-out Animals.” Journal of Biological Chemistry 282 (41): 30014–21. doi:10.1074/jbc.M704817200.

Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:41543093

Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA THE JOURNAL OF BIOLOGICAL CHEMISTRY VOL. 282, NO. 41, pp. 30014–30021, October 12, 2007 © 2007 by The American Society for Biochemistry and Molecular , Inc. Printed in the U.S.A.

Skeletal Muscle Fiber-type Switching, Exercise Intolerance, and Myopathy in PGC-1␣ Muscle-specific Knock-out Animals*□S Received for publication, June 12, 2007, and in revised form, July 5, 2007 Published, JBC Papers in Press, August 16, 2007, DOI 10.1074/jbc.M704817200 Christoph Handschin‡§1, Sherry Chin‡, Ping Li¶, Fenfen Liuʈ, Eleftheria Maratos-Flierʈ, Nathan K. LeBrasseur**, Zhen Yan¶, and Bruce M. Spiegelman‡2 From the ‡Dana-Farber Cancer Institute and Department of , Harvard Medical School, Boston, Massachusetts 02115, §Institute of and Zurich Center for Integrative Human Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland, ¶Department of Medicine, Duke University Medical Center, Durham, North Carolina 27704, ʈDivision of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, and **Diabetes and Metabolism Unit, Boston University School of Medicine, Boston, Massachusetts 02118

The transcriptional coactivator peroxisome proliferator-acti- scription of myofibrillar genes typical of oxidative muscle fibers vated receptor ␥ coactivator 1␣ (PGC-1␣) is a key integrator of (6). Interestingly, MEF2 and PGC-1␣ also control PGC-1␣ gene neuromuscular activity in skeletal muscle. Ectopic expression of transcription in an autoregulatory loop (7, 8). Metabolic genes,

PGC-1␣ in muscle results in increased mitochondrial number including those responsible for mitochondrial oxidative phos- Downloaded from and function as well as an increase in oxidative, fatigue-resistant phorylation, are induced by a transcriptional cascade with muscle fibers. Whole body PGC-1␣ knock-out mice have a very coactivation of the estrogen-related receptor ␣ (ERR␣, official complex phenotype but do not have a marked skeletal muscle nomenclature NR3B1), the nuclear respiratory factor 2 (NRF-2, phenotype. We thus analyzed skeletal muscle-specific PGC-1␣ alternatively called GA-binding protein, GABP), and the ␣ knock-out mice to identify a specific role for PGC-1 in skeletal nuclear respiratory factor 1 (NRF-1) by PGC-1␣ and subse- http://www.jbc.org/ muscle function. These mice exhibit a shift from oxidative type I quent increase in the levels of mitochondrial transcription fac- and IIa toward type IIx and IIb muscle fibers. Moreover, skeletal tor A (TFAM) and mitochondrial transcription specificity fac- muscle-specific PGC-1␣ knock-out animals have reduced tors TFB1M and TFB2M (9–13). Recently, we have found that endurance capacity and exhibit fiber damage and elevated activity-induced remodeling of the postsynaptic side of neuro- mar