Abstract
The glucose transporter 4 (Glut4) mediates insulin‐dependent glucose uptake. Glut4 expression levels are correlated with whole‐body glucose homeostasis. Insulin signaling is known to recruit Glut4 to the cell surface. Expression of Glut4 is subject to tissue‐specific hormonal and metabolic regulation. The molecular mechanisms regulating skeletal muscle Glut4 expression remain to be elucidated. Myostatin (Mstn) is reported to be involved in the regulation of energy metabolism. While elevated Mstn levels in muscle are associated with obesity and type‐2 diabetes in both human and mouse models, Mstn null mice exhibit immunity to dietary‐induced obesity and insulin resistance. The molecular mechanisms by which Mstn initiates the development of insulin resistance and disorders of glucose disposal are not well delineated. Here we investigated effects of Mstn on insulin action in C2C12 cells. Mstn significantly reduced basal and insulin‐induced IRS‐1 tyrosine (Tyr495) phosphorylation, and expression and activation of PI3K, associated with diminished AKT phosphorylation and elevated GSK3β phosphorylation at Ser9. In addition, Mstn inhibited Glut4 mRNA and protein expression, and reduced insulin‐induced Glut4 membrane translocation and glucose uptake. Conversely, SB431542, a Smad2/3 inhibitor, significantly increased cellular response to insulin. Mstn decreased AMP‐activated protein kinase (AMPK) activity accompanied by reduced Glut4 gene expression and glucose uptake, which were partially reversed by AICAR, an AMPK activator. These data suggest that Mstn inhibits Glut4 expression and insulin‐induced Glut4 integration into cytoplasmic membranes and glucose uptake and that these changes are mediated by direct insulin‐desensitizing effect and indirect suppression of AMPK activation.
Highlights
Type 2 diabetes is associated with an impaired rate of insulin-stimulated glucose disposal which has been attributed to insulin resistance in skeletal muscle (Marshall et al 1993; Leguisamo et al 2012)
glucose transporter 4 (Glut4) is expressed in adipose tissue, skeletal muscle and cardiac muscle cells; its expression levels are correlated with whole-body insulin mediated glucose and lipid homeostasis (Liu et al 1993; Ikemoto et al 1995; Ranalletta et al 2007; Atkinson et al 2013)
Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society
Summary
Type 2 diabetes is associated with an impaired rate of insulin-stimulated glucose disposal which has been attributed to insulin resistance in skeletal muscle (Marshall et al 1993; Leguisamo et al 2012). Increased Glut expression in skeletal muscle has been reported to be associated with enhanced insulin sensitivity after exercise (Ikemoto et al 1995; Ivy and Kuo 1998). Incubation of 3T3L1 adipocytes in glucose-free medium downregulates Glut mRNA about 10-fold, whereas readdition of glucose to the starved adipocytes restores Glut mRNA levels (Tordjman et al 1990; Charron et al.1999) These data indicate that metabolic factors, rather than hormonal regulation, are dominant in the regulation of Glut gene expression. Several insulin-independent pathways that regulate glucose metabolism and Glut gene expression have been reported. One of these is AMP-activated protein kinase (AMPK). The effect and underlying mechanism(s) of Mstn action on insulin signaling and metabolism needs to be further elucidated
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