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

Metabolic Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1752, USA.
AJP Cell Physiology (Impact Factor: 3.78). 02/2009; 296(4):C930-40. DOI: 10.1152/ajpcell.00443.2008
Source: PubMed

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.

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    • "There is increasing evidence that developmental plasticity alters the central regulation of homeostatic axes such as those involved in control of blood volume, stress susceptibility and energy balance [82] [83] [84]. Many imprinted genes show high expression in key components of the hypothalamo-pituitary axis (our observations; [74] [85]) and although genetic mouse models of altered dosage at the Dlk1- Dio3, Peg3 and Gnas loci show altered ''set points'' of metabolic axes there is, to our knowledge, currently no data linking changes in the early life environment with changes in the central nervous system expression of imprinted genes [86] [87] [88] [89]. "
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    • "Skeletal-muscle G s α specific have impaired glucose tolerance in the absence of insulin deficiency and resistance, most likely as the result of reduced skeletal muscle mass. In addition, there appears to be a switch of the muscle fiber type towards aerobic, slow twitch (red) fibers even though the muscles have metabolic characteristics more typical of anaerobic, fast-twitch (white) fibers (Chen et al., 2009a). Adipose tissue-specific G s α knockout mice have markedly impaired adipogenesis (Chen et al., 2010). "
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    • "This loss in force is due to altered glucose metabolism and/or lack of circulating insulin since DPH muscles from 12-week diabetic animals supplemented with insulin for 2 weeks presented a complete reversal of this detrimental effect. A recent study in muscle-specific G protein α-subunit (Gsα) knockout mice [20] showed that this disruption of insulin signaling in skeletal muscles resulted in an adaptive fiber-type switch toward increased slow fiber contents in the absence of hyperglycemia. The results in our present study are consistent with this observation and further demonstrate a beneficial effect of the increase in slow fibers on compensating fatigue tolerance in diabetes. "
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