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. 2003 Nov 7;278(45):44298-304.
doi: 10.1074/jbc.M304510200. Epub 2003 Aug 26.

Skeletal muscle reprogramming by activation of calcineurin improves insulin action on metabolic pathways

Jeffrey W Ryder  1 , Rhonda Bassel-Duby, Eric N Olson, Juleen R Zierath
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Free article

Skeletal muscle reprogramming by activation of calcineurin improves insulin action on metabolic pathways

Jeffrey W Ryder et al. J Biol Chem. .
Free article

Abstract

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-gamma 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.

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