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J. Biol. Chem., Vol. 282, Issue 26, 18793-18799, June 29, 2007

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Calcium Induces Increases in Peroxisome Proliferator-activated Receptor Coactivator-1 and Mitochondrial Biogenesis by a Pathway Leading to p38 Mitogen-activated Protein Kinase Activation^*

From the Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110

Previous studies have shown that raising cytosolic calcium in myotubes induces increases in peroxisome proliferator-activated receptor coactivator-1 expression and mitochondrial biogenesis. This finding suggests that the increases in cytosolic calcium in skeletal muscle during exercise may mediate the exercise-induced increase in mitochondria. The initial aim of this study was to determine whether raising calcium in skeletal muscle induces the same adaptations as in myotubes. We found that treatment of rat epitrochlearis muscles with a concentration of caffeine that raises cytosolic calcium to a concentration too low to cause contraction induces increases in peroxisome proliferator-activated receptor coactivator-1 expression and mitochondrial biogenesis. Our second aim was to elucidate the pathway by which calcium induces these adaptations. Raising cytosolic calcium has been shown to activate calcium/calmodulin-dependent protein kinase in muscle. In the present study raising cytosolic calcium resulted in increases in phosphorylation of p38 mitogen-activated protein kinase and activating transcription factor-2, which were blocked by the calcium/calmodulin-dependent protein kinase inhibitor KN93 and by the p38 mitogen-activated protein kinase inhibitor SB202190. The increases in peroxisome proliferator-activated receptor coactivator-1 expression and mitochondrial biogenesis were also prevented by inhibiting p38 activation. We interpret these findings as evidence that p38 mitogen-activated protein kinase is downstream of calcium/calmodulin-dependent protein kinase in a signaling pathway by which increases in cytosolic calcium lead to increases in peroxisome proliferator-activated receptor coactivator-1 expression and mitochondrial biogenesis in muscle.

Received for publication, December 7, 2006 , and in revised form, April 26, 2007.

^* This research was supported by National Institutes of Health Grant AG00425. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by an American Diabetes Association Mentor-based Postdoctoral Fellowship and by NIA, National Institutes of Health Institutional National Research Service Award AG00078 and individual National Research Service Award Grant DK070425.

² Supported by NIA, National Institutes of Health Institutional National Research Service Award AG00078.

³ To whom correspondence should be addressed: Washington University School of Medicine, Division of Geriatrics and Nutritional Sciences, Campus Box 8113, 4566 Scott Ave., St. Louis, MO 63110. Tel.: 314-362-3506; Fax: 314-362-7657; E-mail: jhollosz{at}im.wustl.edu.

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