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Science 12 April 2002:
Vol. 296. no. 5566, pp. 349 - 352
DOI: 10.1126/science.1071163
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Reports

Regulation of Mitochondrial Biogenesis in Skeletal Muscle by CaMK

Hai Wu,1 Shane B. Kanatous,1 Frederick A. Thurmond,1 Teresa Gallardo,1 Eiji Isotani,2 Rhonda Bassel-Duby,1 R. Sanders Williams3*

Endurance exercise training promotes mitochondrial biogenesis in skeletal muscle and enhances muscle oxidative capacity, but the signaling mechanisms involved are poorly understood. To investigate this adaptive process, we generated transgenic mice that selectively express in skeletal muscle a constitutively active form of calcium/calmodulin-dependent protein kinase IV (CaMKIV*). Skeletal muscles from these mice showed augmented mitochondrial DNA replication and mitochondrial biogenesis, up-regulation of mitochondrial enzymes involved in fatty acid metabolism and electron transport, and reduced susceptibility to fatigue during repetitive contractions. CaMK induced expression of peroxisome proliferator-activated receptor gamma  coactivator 1 (PGC-1), a master regulator of mitochondrial biogenesis in vivo, and activated the PGC-1 gene promoter in cultured myocytes. Thus, a calcium-regulated signaling pathway controls mitochondrial biogenesis in mammalian cells.

1 Departments of Internal Medicine and Molecular Biology,
2 Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
3 Duke University Medical Center School of Medicine, Durham, NC 27710, USA.
*   To whom correspondence should be addressed. E-mail: rswilliams{at}mc.duke.edu

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Science. ISSN 0036-8075 (print), 1095-9203 (online)