Skeletal muscle reprogramming by activation of calcineurin improves insulin action on metabolic pathways.
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.
Ryder
Jeffrey W
JW
Department of Physiology and Pharmacology, Section of Integrative Physiology, Karolinska Institutet, 17177 Stockholm, Sweden. jeff.ryder@fyfa.ki.se
Bassel-Duby
Rhonda
R
Olson
Eric N
EN
Zierath
Juleen R
JR
D000818:Animals; D019703:Calcineurin / Q000235:genetics* / Q000378:metabolism*; D003847:Deoxyglucose / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects; D004789:Enzyme Activation; D015870:Gene Expression; D018149:Glucose Intolerance / Q000209:etiology; D051275:Glucose Transporter Type 4; D006003:Glycogen / Q000032:analysis; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D051379:Mice; D008822:Mice, Transgenic; D009004:Monosaccharide Transport Proteins / Q000032:analysis; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D019301:Oleic Acid / Q000378:metabolism; D010084:Oxidation-Reduction; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000032:analysis; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000032:analysis; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000378:metabolism
D019703:Calcineurin; D003847:Deoxyglucose; D004041:Dietary Fats; D051275:Glucose Transporter Type 4; D006003:Glycogen; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D019301:Oleic Acid; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin; D014443:Tyrosine; D015091:beta-Alanine; C526295:Irs1 protein, mouse; C495693:Slc2a4 protein, mouse; C012924:2,2-dimethyl-beta-alanine