Invited Review: Regulation of skeletal muscle GLUT-4 expression by exercise

2002 ◽  
Vol 93 (2) ◽  
pp. 782-787 ◽  
Author(s):  
G. Lynis Dohm
Keyword(s):  
Skeletal Muscle ◽  
Transcriptional Control ◽  
Therapeutic Strategies ◽  
Glucose Disposal ◽  
Research Needs ◽  
Maximal Rate ◽  
Myocyte Enhancer Factor 2 ◽  
Glut 4 ◽  
Myocyte Enhancer Factor ◽  
Enhancer Factor

The amount of GLUT-4 protein is a primary factor in determining the maximal rate of glucose transport into skeletal muscle. Therefore, it is important that we understand how exercise regulates GLUT-4 expression so that therapeutic strategies can be designed to increase muscle glucose disposal as a treatment for diabetes. Muscle contraction increases the rates of GLUT-4 transcription and translation. Transcriptional control likely requires at least two DNA binding proteins, myocyte enhancer factor-2 and GLUT-4 enhancer factor, which bind to the promoter. Increased GLUT-4 expression may be mediated by the enzyme AMP-activated kinase, which is activated during exercise and has been demonstrated to increase GLUT-4 transcription. Further research needs to be done to investigate whether AMP-activated kinase activates myocyte enhancer factor-2 and GLUT-4 enhancer factor to increase transcription of the GLUT-4 gene.

scholarly journals Direct Interaction between Myocyte Enhancer Factor 2 (MEF2) and Protein Phosphatase 1α Represses MEF2-Dependent Gene Expression

2009 ◽  
Vol 29 (12) ◽  
pp. 3355-3366 ◽  
Author(s):  
R. L. S. Perry ◽  
C. Yang ◽  
N. Soora ◽  
J. Salma ◽  
M. Marback ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Protein Interactions ◽  
Protein Phosphatase ◽  
Hippocampal Neurons ◽  
Neuronal Cell ◽  
Direct Interaction ◽  
Myocyte Enhancer Factor 2 ◽  
Myocyte Enhancer Factor ◽  
Enhancer Factor

ABSTRACT The myocyte enhancer factor 2 (MEF2) transcription factors play important roles in neuronal, cardiac, and skeletal muscle tissues. MEF2 serves as a nuclear sensor, integrating signals from several signaling cascades through protein-protein interactions with kinases, chromatin remodeling factors, and other transcriptional regulators. Here, we report a novel interaction between the catalytic subunit of protein phosphatase 1α (PP1α) and MEF2. Interaction occurs within the nucleus, and binding of PP1α to MEF2 potently represses MEF2-dependent transcription. The interaction utilizes uncharacterized domains in both PP1α and MEF2, and PP1α phosphatase activity is not obligatory for MEF2 repression. Moreover, a MEF2-PP1α regulatory complex leads to nuclear retention and recruitment of histone deacetylase 4 to MEF2 transcription complexes. PP1α-mediated repression of MEF2 overrides the positive influence of calcineurin signaling, suggesting PP1α exerts a dominant level of control over MEF2 function. Indeed, PP1α-mediated repression of MEF2 function interferes with the prosurvival effect of MEF2 in primary hippocampal neurons. The PP1α-MEF2 interaction constitutes a potent locus of control for MEF2-dependent gene expression, having potentially important implications for neuronal cell survival, cardiac remodeling in disease, and terminal differentiation of vascular, cardiac, and skeletal muscle.

scholarly journals Molecular cloning of up-regulated cytoskeletal genes from regenerating skeletal muscle: potential role of myocyte enhancer factor 2 proteins in the activation of muscle-regeneration-associated genes

1997 ◽  
Vol 325 (1) ◽  
pp. 87-93 ◽  
Author(s):  
Waleed M. AKKILA ◽  
Rebecca L. CHAMBERS ◽  
Olga I. ORNATSKY ◽  
John C. McDERMOTT
Keyword(s):  
Skeletal Muscle ◽  
Transcriptional Activation ◽  
Regulatory Protein ◽  
Cdna Clones ◽  
Myocyte Enhancer Factor 2 ◽  
Consensus Binding Site ◽  
Mobility Shift ◽  
Adult Skeletal Muscle ◽  
Myocyte Enhancer Factor ◽  
Enhancer Factor

A subtractive hybridization and cloning strategy was used to identify genes that are up-regulated in regenerating compared with normal skeletal muscle. The gastrocnemius muscle of CD1 mice was injected with a myotoxic agent (BaCl2). A cDNA library was constructed from the regenerating muscle, and was screened with subtracted probes enriched in genes up-regulated during regeneration. Cofilin and vimentin cDNA clones were isolated. Both cofilin and vimentin were demonstrated to be overexpressed in regenerating compared with non-regenerating muscle (17-fold and 19-fold induction respectively). Cofilin and vimentin mRNAs also exhibited an increased expression in C2C12 myoblasts and a decreased expression in differentiated myotubes. Analysis of the regeneration-induced vimentin enhancer/promoter region revealed a consensus binding site for the myocyte enhancer factor 2 (MEF2) transcription factors. Electrophoretic mobility-shift assays and in vivo reporter assays revealed that MEF2 DNA-binding activity and transcriptional activation are increased in regenerating skeletal muscle, indicating that they may play a role in the activation of muscle genes during regeneration. These data suggest that both cofilin (an actin-regulatory protein) and vimentin (an intermediate filament) may be key components of the cytoskeletal reorganization that mediates muscle cell development and adult skeletal-muscle repair.

Regulation of muscle GLUT-4 transcription by AMP-activated protein kinase

2001 ◽  
Vol 91 (3) ◽  
pp. 1073-1083 ◽  
Author(s):  
Donghai Zheng ◽  
Paul S. MacLean ◽  
Steven C. Pohnert ◽  
John B. Knight ◽  
Ann Louise Olson ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Consensus Sequence ◽  
Proximal Promoter ◽  
Response To Treatment ◽  
Mrna Levels ◽  
Myocyte Enhancer Factor 2 ◽  
Glut 4 ◽  
Myocyte Enhancer Factor ◽  
Amp Activated Protein Kinase ◽  
Enhancer Factor

Skeletal muscle GLUT-4 transcription in response to treatment with 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), a known activator of AMP-activated protein kinase (AMPK), was studied in rats and mice. The increase in GLUT-4 mRNA levels in response to a single subcutaneous injection of AICAR, peaked at 13 h in white and red quadriceps muscles but not in the soleus muscle. The mRNA level of chloramphenicol acyltransferase reporter gene which is driven by 1,154 or 895 bp of the human GLUT-4 proximal promoter was increased in AICAR-treated transgenic mice, demonstrating the transcriptional upregulation of the GLUT-4 gene by AICAR. However, this induction of transcription was not apparent with 730 bp of the promoter. In addition, nuclear extracts from AICAR-treated mice bound to the consensus sequence of myocyte enhancer factor-2 (from −473 to −464) to a greater extent than from saline-injected mice. Thus AMP-activated protein kinase activation by AICAR increases GLUT-4 transcription by a mechanism that requires response elements within 895 bp of human GLUT-4 proximal promoter and that may be cooperatively mediated by myocyte enhancer factor-2.

Regulation of muscle GLUT4 enhancer factor and myocyte enhancer factor 2 by AMP-activated protein kinase

2005 ◽  
Vol 289 (6) ◽  
pp. E1071-E1076 ◽  
Author(s):  
Burton F. Holmes ◽  
David P. Sparling ◽  
Ann Louise Olson ◽  
William W. Winder ◽  
G. Lynis Dohm
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Glucose Transporter ◽  
Myocyte Enhancer Factor 2 ◽  
Consensus Sequences ◽  
Glut4 Expression ◽  
Myocyte Enhancer Factor ◽  
Amp Activated Protein Kinase ◽  
Enhancer Factor

As the primary glucose transporter in skeletal muscle, GLUT4 is an important factor in the regulation of blood glucose. We previously reported that stimulation of AMP-activated protein kinase (AMPK) with 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) increased GLUT4 expression in muscle. GLUT4 enhancer factor (GEF) and myocyte enhancer factor 2 (MEF2) have been shown to be important for normal GLUT4 expression because deletion or truncation of the consensus sequences on the promoter causes depressed GLUT4 mRNA expression. This led to the current study to investigate possible roles for GEF and MEF2 in mediating the activation of GLUT4 gene transcription in response to AMPK. Here we show that, although AMPK does not appear to phosphorylate MEF2A, AMPK directly phosphorylates the GEF protein in vitro. MEF2 and GEF are activated in response to AMPK as we observed translocation of both to the nucleus after AICAR treatment. Nuclear MEF2 protein content was increased after 2 h, and GEF protein was increased in the nucleus 1 and 2 h post-AICAR treatment. Last, GEF and MEF2 increase in binding to the GLUT4 promoter within 2 h after AICAR treatment. Thus we conclude that GEF and MEF2 mediate the AMPK-induced increase in transcription of skeletal muscle GLUT4. AMPK can phosphorylate GEF and in response to AICAR, GEF, and MEF2 translocate to the nucleus and have increased binding to the GLUT4 promoter.

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