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

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

Research output: Contribution to journalArticle

29 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)C930-C940
JournalAmerican Journal of Physiology - Cell Physiology
Volume296
Issue number4
DOIs
StatePublished - Apr 1 2009
Externally publishedYes

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Glucose Intolerance
Insulin Resistance
Skeletal Muscle
Muscles
Glucose
AMP-Activated Protein Kinases
Insulin
MM Form Creatine Kinase
Ideal Body Weight
Peroxisome Proliferator-Activated Receptors
Myosin Heavy Chains
Protein Subunits
Body Composition
GTP-Binding Proteins
Nonesterified Fatty Acids
Knockout Mice
Energy Metabolism
Transgenic Mice
Protein Isoforms
Triglycerides

Keywords

  • Atrophy
  • G protein

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

Cite this

Gsα deficiency in skeletal muscle leads to reduced muscle mass, fiber-type switching, and glucose intolerance without insulin resistance or deficiency. / Chen, Min; Feng, Han Zhong; Gupta, Divakar; Kelleher, James; Dickerson, Kathryn E.; Wang, Jie; Hunt, Desmond; Jou, William; Gavrilova, Oksana; Jin, Jian Ping; Weinstein, Lee S.

In: American Journal of Physiology - Cell Physiology, Vol. 296, No. 4, 01.04.2009, p. C930-C940.

Research output: Contribution to journalArticle

Chen, Min ; Feng, Han Zhong ; Gupta, Divakar ; Kelleher, James ; Dickerson, Kathryn E. ; Wang, Jie ; Hunt, Desmond ; Jou, William ; Gavrilova, Oksana ; Jin, Jian Ping ; Weinstein, Lee S. / Gsα deficiency in skeletal muscle leads to reduced muscle mass, fiber-type switching, and glucose intolerance without insulin resistance or deficiency. In: American Journal of Physiology - Cell Physiology. 2009 ; Vol. 296, No. 4. pp. C930-C940.
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AU - Hunt, Desmond

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AB - 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.

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