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Science 296 (5566): 349-352

Copyright © 2002 by the American Association for the Advancement of Science

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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M. Oh, I. I. Rybkin, V. Copeland, M. P. Czubryt, J. M. Shelton, E. van Rooij, J. A. Richardson, J. A. Hill, L. J. De Windt, R. Bassel-Duby, et al. (2005)
Mol. Cell. Biol. 25, 6629-6638
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Comparison of gene expression of 2-mo denervated, 2-mo stimulated-denervated, and control rat skeletal muscles.
T. Y. Kostrominova, D. E. Dow, R. G. Dennis, R. A. Miller, and J. A. Faulkner (2005)
Physiol Genomics 22, 227-243
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The Conserved Mec1/Rad53 Nuclear Checkpoint Pathway Regulates Mitochondrial DNA Copy Number in Saccharomyces cerevisiae.
S. D. Taylor, H. Zhang, J. S. Eaton, M. S. Rodeheffer, M. A. Lebedeva, T. W. O'Rourke, W. Siede, and G. S. Shadel (2005)
Mol. Biol. Cell 16, 3010-3018
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Exercise Stimulates Pgc-1{alpha} Transcription in Skeletal Muscle through Activation of the p38 MAPK Pathway.
T. Akimoto, S. C. Pohnert, P. Li, M. Zhang, C. Gumbs, P. B. Rosenberg, R. S. Williams, and Z. Yan (2005)
J. Biol. Chem. 280, 19587-19593
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Aging muscle.
K S. Nair (2005)
Am J Clin Nutr 81, 953-963
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Control of muscle bioenergetic gene expression: implications for allometric scaling relationships of glycolytic and oxidative enzymes.
C. D. Moyes and C. M. R. LeMoine (2005)
J. Exp. Biol. 208, 1601-1610
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Subsarcolemmal and intermyofibrillar mitochondria play distinct roles in regulating skeletal muscle fatty acid metabolism.
T. R. Koves, R. C. Noland, A. L. Bates, S. T. Henes, D. M. Muoio, and R. N. Cortright (2005)
Am J Physiol Cell Physiol 288, C1074-C1082
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Mechanisms of Insulin Resistance in Humans and Possible Links With Inflammation.
D. B. Savage, K. F. Petersen, and G. I. Shulman (2005)
Hypertension 45, 828-833
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Gene regulation by NMDA receptor activation in the SDN-POA neurons of male rats during sexual development.
H.-K. Hsu, P.-L. Shao, K.-L. Tsai, H.-C. Shih, T.-Y. Lee, and C. Hsu (2005)
J. Mol. Endocrinol. 34, 433-445
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Increased Mitochondrial DNA Content in Saliva Associated with Head and Neck Cancer.
W.-W. Jiang, B. Masayesva, M. Zahurak, A. L. Carvalho, E. Rosenbaum, E. Mambo, S. Zhou, K. Minhas, N. Benoit, W. H. Westra, et al. (2005)
Clin. Cancer Res. 11, 2486-2491
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Effects of weight loss and physical activity on skeletal muscle mitochondrial function in obesity.
E. V. Menshikova, V. B. Ritov, F. G. S. Toledo, R. E. Ferrell, B. H. Goodpaster, and D. E. Kelley (2005)
Am J Physiol Endocrinol Metab 288, E818-E825
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Inhibition of cross-bridge formation has no effect on contraction-associated phosphorylation of p38 MAPK in mouse skeletal muscle.
J. N. Dentel, S. G. Blanchard, D. P. Ankrapp, L. R. McCabe, and R. W. Wiseman (2005)
Am J Physiol Cell Physiol 288, C824-C830
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