Calcineurin Regulates Skeletal Muscle Metabolism via Coordinated Changes in Gene Expression

• Published in: The Journal of biological chemistry 2007-01, Vol.282 (3), p.1607-1614
• Main Authors: Long, Yun Chau, Glund, Stephan, Garcia-Roves, Pablo M., Zierath, Juleen R.
• Format: Article
• Language: English
• Subjects: Animals; Calcineurin - pharmacology; Female; Gene Expression Regulation; Glucose - metabolism; Glycogen - metabolism; Heat-Shock Proteins - metabolism; Lipid Metabolism; Mice; Mice, Transgenic; Muscle, Skeletal - metabolism; Oxidative Phosphorylation; Oxygen - metabolism; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; PPAR gamma - metabolism; Protein Kinases - metabolism; Transcription Factors - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M609208200

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 PPARγ coactivator 1α (PGC1α) are transcription regulators for the expression of metabolic and mitochondrial genes. Consistent with changes in the gene-regulatory program, calcineurin promoted the expression of PPARα, PPARδ, and PPARγ coactivator 1α 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.