Skeletal Muscle Reprogramming by Activation of Calcineurin Improves Insulin Action on Metabolic Pathways

• Published in: The Journal of biological chemistry 2003-11, Vol.278 (45), p.44298-44304
• Main Authors: Ryder, Jeffrey W., Bassel-Duby, Rhonda, Olson, Eric N., Zierath, Juleen R.
• Format: Article
• Language: English
• Subjects: Animals; beta-Alanine - analogs & derivatives; beta-Alanine - metabolism; Calcineurin - genetics; Calcineurin - metabolism; Deoxyglucose - metabolism; Dietary Fats - administration & dosage; Dietary Fats - adverse effects; Enzyme Activation; Gene Expression; Glucose Intolerance - etiology; Glucose Transporter Type 4; Glycogen - analysis; Insulin - pharmacology; Insulin Receptor Substrate Proteins; Medicin och hälsovetenskap; Mice; Mice, Transgenic; Monosaccharide Transport Proteins - analysis; Muscle Proteins; Muscle, Skeletal - chemistry; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Oleic Acid - metabolism; Oxidation-Reduction; Phosphatidylinositol 3-Kinases - metabolism; Phosphoproteins - analysis; Phosphorylation; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins - analysis; Proto-Oncogene Proteins c-akt; Receptor, Insulin - metabolism; Signal Transduction; Tyrosine - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M304510200

The protein phosphatase calcineurin is a signaling intermediate that induces the transformation of fast-twitch skeletal muscle fibers to a slow-twitch phenotype. This reprogramming of the skeletal muscle gene expression profile may have therapeutic applications for metabolic disease. Insulin-stimulated glucose uptake in skeletal muscle is both impaired in individuals with type II diabetes mellitus and positively correlated with the percentage of slow-versus fast-twitch muscle fibers. Using transgenic mice expressing activated calcineurin in skeletal muscle, we report that skeletal muscle reprogramming by calcineurin activation leads to improved insulin-stimulated 2-deoxyglucose uptake in extensor digitorum longus (EDL) muscles compared with wild-type mice, concomitant with increased protein expression of the insulin receptor, Akt, glucose transporter 4, and peroxisome proliferator-activated receptor-γ co-activator 1. Transgenic mice exhibited elevated glycogen deposition, enhanced amino acid uptake, and increased fatty acid oxidation in EDL muscle. When fed a high-fat diet, transgenic mice maintained superior rates of insulin-stimulated glucose uptake in EDL muscle and were protected against diet-induced glucose intolerance. These results validate calcineurin as a target for enhancing insulin action in skeletal muscle.