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Gsα deficiency in skeletal muscle leads to reduced muscle mass, fiber-type switching, and glucose intolerance without insulin resistance or deficiency

By Min Chen, Han-Zhong Feng, Divakar Gupta, James Kelleher, Kathryn E. Dickerson, Jie Wang, Desmond Hunt, William Jou, Oksana Gavrilova, Jian-Ping Jin and Lee S. Weinstein

Abstract

The ubiquitously expressed G protein α-subunit Gsα is required for receptor-stimulated intracellular cAMP responses and is an important regulator of energy and glucose metabolism. We have generated skeletal muscle-specific Gsα-knockout (KO) mice (MGsKO) by mating Gsα-floxed mice with muscle creatine kinase-cre transgenic mice. MGsKO mice had normal body weight and composition, and their serum glucose, insulin, free fatty acid, and triglyceride levels were similar to that of controls. However, MGsKO mice were glucose intolerant despite the fact that insulin sensitivity and glucose-stimulated insulin secretion were normal, suggesting an insulin-independent mechanism. Isolated muscles from MGsKO mice had increased basal glucose uptake and normal responses to a stimulator of AMP-activated protein kinase (AMPK), which indicates that AMPK and its downstream pathways are intact. Compared with control mice, MGsKO mice had reduced muscle mass with decreased cross-sectional area and force production. In addition, adult MGsKO mice showed an increased proportion of type I (slow-twitch, oxidative) fibers based on kinetic properties and myosin heavy chain isoforms, despite the fact that these muscles had reduced expression of peroxisome proliferator-activated receptor coactivator protein-1α (PGC-1α) and reduced mitochondrial content and oxidative capacity. Therefore Gsα deficiency led to fast-to-slow fiber-type switching, which appeared to be dissociated from the expected change in oxidative capacity. MGsKO mice are a valuable model for future studies of the role of Gsα signaling pathways in skeletal muscle adaptation and their effects on whole body metabolism

Topics: Muscle Cell Biology and Cell Motility
Publisher: American Physiological Society
OAI identifier: oai:pubmedcentral.nih.gov:2670650
Provided by: PubMed Central
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