title: G(s)alpha deficiency in skeletal muscle leads to reduced muscle mass, fiber-type switching, and glucose intolerance without insulin resistance or deficiency.
abstract: The ubiquitously expressed G protein alpha-subunit G(s)alpha is required for receptor-stimulated intracellular cAMP responses and is an important regulator of energy and glucose metabolism. We have generated skeletal muscle-specific G(s)alpha-knockout (KO) mice (MGsKO) by mating G(s)alpha-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-1alpha (PGC-1alpha) and reduced mitochondrial content and oxidative capacity. Therefore G(s)alpha 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 G(s)alpha signaling pathways in skeletal muscle adaptation and their effects on whole body metabolism.
authors.affiliation: Metabolic Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1752, USA. minc@intra.niddk.nih.gov
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.forename: Han-Zhong
authors.initials: HZ
authors.lastname: Feng
authors.forename: Divakar
authors.initials: D
authors.lastname: Gupta
authors.forename: James
authors.initials: J
authors.lastname: Kelleher
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Dickerson
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.forename: Desmond
authors.initials: D
authors.lastname: Hunt
authors.forename: William
authors.initials: W
authors.lastname: Jou
authors.forename: Oksana
authors.initials: O
authors.lastname: Gavrilova
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Jin
authors.forename: Lee S
authors.initials: LS
authors.lastname: Weinstein
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002864:Chromogranins; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000172:deficiency* / Q000235:genetics; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction; D018656:Muscle Fibers, Fast-Twitch / Q000378:metabolism* / Q000473:pathology; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism* / Q000473:pathology; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D018995:Myosin Heavy Chains / Q000378:metabolism; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors
chemical_list: D001786:Blood Glucose; D002864:Chromogranins; D005227:Fatty Acids; D007328:Insulin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D055372:AMP-Activated Protein Kinases; C498642:Gnas protein, mouse; D018995:Myosin Heavy Chains; D019205:GTP-Binding Protein alpha Subunits, Gs