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J. Biol. Chem., Vol. 282, Issue 3, 1607-1614, January 19, 2007

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Calcineurin Regulates Skeletal Muscle Metabolism via Coordinated Changes in Gene Expression^*

From the Department of Molecular Medicine and Surgery, Section of Integrative Physiology, Karolinska Institutet, von Eulers väg 4, 4th Floor, Stockholm S-171 77, Sweden

The metabolic property of skeletal muscle adapts in response to an increased physiological demand by altering substrate utilization and gene expression. The calcium-regulated serine/threonine protein phosphatase calcineurin has been implicated in the transduction of motor neuron signals to alter gene expression programs in skeletal muscle. We utilized transgenic mice that overexpress an activated form of calcineurin in skeletal muscle (MCK-CnA*) to investigate the impact of calcineurin activation on metabolic properties of skeletal muscle. Activation of calcineurin increased glucose incorporation into glycogen and lipid oxidation in skeletal muscle. Activated calcineurin suppressed skeletal muscle glucose oxidation and increased lactate release. The enhancement in lipid oxidation was supported by increased expression of genes for lipid metabolism and mitochondrial oxidative phosphorylation. In a reciprocal fashion, several genes of glycolysis were down-regulated, whereas pyruvate dehydrogenase kinase 4 was markedly induced. This expression pattern was associated with decreased glucose utilization and enhanced glycogen storage. The peroxisome proliferator-activated receptors (PPARs) and PPAR coactivator 1 (PGC1) are transcription regulators for the expression of metabolic and mitochondrial genes. Consistent with changes in the gene-regulatory program, calcineurin promoted the expression of PPAR, PPAR, and PPAR coactivator 1 in skeletal muscle. These results provide evidence that calcineurin-mediated skeletal muscle reprogramming induces the expression of several transcription regulators that coordinate changes in the expression of genes for lipid and glucose metabolism, which in turn alters energy substrate utilization in skeletal muscle.

Received for publication, September 28, 2006 , and in revised form, November 14, 2006.

^* This work was supported by the Swedish Research Council, the Swedish Diabetes Association, Swedish Center for Sports Research, the Foundation for Scientific Studies of Diabetology, the Strategic Research Foundation (INGVAR II), and the Commission of the European Communities (Contract LSHM-CT-2004-005272 EXGENESIS, Contract LSHM-CT-2004-512013 EUGENE2, and Contract LSHM-CT-2004-512013 EUGENEHEART). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1.

¹ Supported by a scholarship from the Karolinska Institutet.

² To whom correspondence should be addressed. Tel.: 46-8-524-875-81; Fax: 46-8-33-54-36; E-mail: Juleen.Zierath{at}ki.se.

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