Exercise and Myocyte Enhancer Factor 2 Regulation in Human Skeletal Muscle

Abstract

Overexpression of GLUT4 in skeletal muscle enhances whole-body insulin action. Exercise increases GLUT4 gene and protein expression, and a binding site for the myocyte enhancer factor 2 (MEF-2) is required on the GLUT4 promoter for this response. However, the molecular mechanisms involved remain elusive. In various cell systems, MEF-2 regulation is a balance between transcriptional repression by histone deacetylases (HDACs) and transcriptional activation by the nuclear factor of activated T-cells (NFAT), peroxisome proliferator-activated receptor-␥ coactivator 1 (PGC-1), and the p38 mitogen-activated protein kinase. The purpose of this study was to determine if these same mechanisms regulate MEF-2 in contracting human skeletal muscle. Seven subjects performed 60 min of cycling at ϳ70% of Vo 2peak . After exercise, HDAC5 was dissociated from MEF-2 and exported from the nucleus, whereas nuclear PGC-1 was associated with MEF-2. Exercise increased total and nuclear p38 phosphorylation and association with MEF-2, without changes in total or nuclear p38 protein abundance. This result was associated with p38 sequence-specific phosphorylation of MEF-2 and an increase in GLUT4 mRNA. Finally, we found no role for NFAT in MEF-2 regulation. From these data, it appears that HDAC5, PGC-1, and p38 regulate MEF-2 and could be potential targets for modulating GLUT4 expression.

Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase

“…However, in a recent study, Bdnf mRNA was shown to be expressed in murine skeletal muscle and was increased by inhibition of histone deacetylases [24]. Since exercise can inhibit histone deacetylases [25], the possibility exists that the increase in circulating BDNF in humans during exercise may originate in the contracting muscle cells and that BDNF may be a novel contraction-induced myokine. Accordingly, we aimed to investigate whether skeletal muscle would produce BDNF in response to exercise.…”

p38 Mitogen-activated Protein Kinase Plays an Inhibitory Role in Hepatic Lipogenesis

“…Because p38 has been shown to play a stimulatory role in glucose uptake in skeletal muscles and adipocytes through expression of Glut4 (41)(42)(43)(44)(45)(46)(47)(48)(49), the blockade of p38 may reduce glucose uptake in theses tissues, resulting in excess glucose supply. The excess glucose is then converted into fatty acids and contributes to the development of hypertriglyceridemia and fatty liver.…”

PGC-1α Mediated Muscle Aerobic Adaptations to Exercise, Heat and Cold Exposure

“…Recent studies have identified several PGC-1α isoforms (Popov et al, 2014;Tadaishi et al, 2011;Ydfors et al, 2013) which are mostly exercise sensitive and collectively contribute to the overall increase in skeletal muscle PGC-1α mRNA observed following exercise (Baar et al, 2002;McGee & Hargreaves, 2004;Pilegaard et al, 2003;Russell et al, 2005). However, PGC-1α protein content may (Mathai et al, 2008) or may not (McGee & Hargreaves, 2004) be up-regulated following acute exercise, indicating that initial increases in PGC-1α mRNA do not necessarily lead to increased protein expression.…”

“…However, PGC-1α protein content may (Mathai et al, 2008) or may not (McGee & Hargreaves, 2004) be up-regulated following acute exercise, indicating that initial increases in PGC-1α mRNA do not necessarily lead to increased protein expression. Paradoxically, gene expression of Tfam, Cyt c and the transcriptional activity of NRFs all increased shortly after exercise Wright et al, 2007b) indicating that initial events in mitochondrial biogenesis are mediated by the activation/phosphorylation of existing muscle PGC-1α content.…”