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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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Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1.
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PNAS 100, 8466-8471
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Dietary fat interacts with QTLs controlling induction of Pgc-1{alpha} and Ucp1 during conversion of white to brown fat.
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Physiol Genomics 14, 139-147
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PNAS 100, 7111-7116
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PPARgamma coactivator-1alpha expression during thyroid hormone- and contractile activity-induced mitochondrial adaptations.
I. Irrcher, P. J. Adhihetty, T. Sheehan, A.-M. Joseph, and D. A. Hood (2003)
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Adenylate Kinase 1 Deficiency Induces Molecular and Structural Adaptations to Support Muscle Energy Metabolism.
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Raising Ca2+ in L6 myotubes mimics effects of exercise on mitochondrial biogenesis in muscle.
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FASEB J 17, 675-681
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Alterations in Slow-Twitch Muscle Phenotype in Transgenic Mice Overexpressing the Ca2+ Buffering Protein Parvalbumin.
E. R Chin, R. W Grange, F. Viau, A. R Simard, C. Humphries, J. Shelton, R. Bassel-Duby, R S. Williams, and R. N Michel (2003)
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Regulation of peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha ) and mitochondrial function by MEF2 and HDAC5.
M. P. Czubryt, J. McAnally, G. I. Fishman, and E. N. Olson (2003)
PNAS 100, 1711-1716
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Mitochondrial Biogenesis in Mammals: The Role of Endogenous Nitric Oxide.
E. Nisoli, E. Clementi, C. Paolucci, V. Cozzi, C. Tonello, C. Sciorati, R. Bracale, A. Valerio, M. Francolini, S. Moncada, et al. (2003)
Science 299, 896-899
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Exercise induces transient transcriptional activation of the PGC-1{alpha} gene in human skeletal muscle.
H. Pilegaard, B. Saltin, and P D. Neufer (2003)
J. Physiol. 546, 851-858
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AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation.
H. Zong, J. M. Ren, L. H. Young, M. Pypaert, J. Mu, M. J. Birnbaum, and G. I. Shulman (2002)
PNAS 99, 15983-15987
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Phosphocreatine kinetics at the onset of contractions in skeletal muscle of MM creatine kinase knockout mice.
B. B. Roman, R. A. Meyer, and R. W. Wiseman (2002)
Am J Physiol Cell Physiol 283, C1776-C1783
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