In previously funded research we discovered that exercise training increases muscle GLUT4 protein approximately 2-3 fold and this change is accompanied by greater insulin sensitivity in human subjects and increased muscle glucose transport rates in experimental animals. We recently discovered that treating mice with AICAR (an activator of muscle AMP-kinase) also causes GLUT4 gene transcription to be increased. To understand how GLUT4 gene expression is regulated we propose investigating transcription in physiological situations where GLUT4 is differentially expressed. GLUT4 protein is higher in red muscle than white muscle, is increased by exercise and is decreased by denervation. The evidence that the transcription factor MEF2 is important in regulation of GLUT4 gene expression is very strong. Thus, it is possible that MEF2 is more active (binds to the GLUT4 promoter to turn on transcription) in red muscle fibers and in exercised muscle. Since energy charge (ATP/AMP) and calcium concentrations are changed in exercising muscle, we believe that these are good signal candidates. Thus, we plan to test the role of AMP-activated kinase (AMPK), calcium/calmodulin-activated kinase (CaM kinase) and calcineurin (a calcium/calmodulin-activated phosphatase) in modulating MEF2 in muscle to increase GLUT4 transcription in red muscle fibers and exercising muscle and decrease GLUT4 expression in denervated muscle. Transgenic animals that express inactive AMPK, activated CaM kinase, and activated calcineurin will be used to study the mechanism of regulation of GLUT4 gene transcription. These studies will provide important general information about mechanisms of adaptation to exercise. There are a large number of genes that are regulated in response to exercise and finding the transcription factor(s) that regulates GLUT4 will provide information that may be important to other adaptive mechanisms. Thus, we feel that the proposed mechanistic studies will provide information that will improve health care for diabetics and increase our knowledge about how the muscle adapts to exercise.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK038416-16
Application #
6607606
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Program Officer
Laughlin, Maren R
Project Start
1987-04-01
Project End
2006-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
16
Fiscal Year
2003
Total Cost
$228,950
Indirect Cost
Name
East Carolina University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
607579018
City
Greenville
State
NC
Country
United States
Zip Code
27858
Holmes, Burton F; Lang, David B; Birnbaum, Morris J et al. (2004) AMP kinase is not required for the GLUT4 response to exercise and denervation in skeletal muscle. Am J Physiol Endocrinol Metab 287:E739-43
Holmes, Burton; Dohm, G Lynis (2004) Regulation of GLUT4 gene expression during exercise. Med Sci Sports Exerc 36:1202-6
MacLean, Paul S; Zheng, Donghai; Jones, Jared P et al. (2002) Exercise-induced transcription of the muscle glucose transporter (GLUT 4) gene. Biochem Biophys Res Commun 292:409-14
Zheng, D; MacLean, P S; Pohnert, S C et al. (2001) Regulation of muscle GLUT-4 transcription by AMP-activated protein kinase. J Appl Physiol 91:1073-83
Hortobagyi, T; Dempsey, L; Fraser, D et al. (2000) Changes in muscle strength, muscle fibre size and myofibrillar gene expression after immobilization and retraining in humans. J Physiol 524 Pt 1:293-304
Zhou, Q; Dolan, P L; Dohm, G L (1999) Dephosphorylation increases insulin-stimulated receptor kinase activity in skeletal muscle of obese Zucker rats. Mol Cell Biochem 194:209-16
Muoio, D M; Dohm, G L; Tapscott, E B et al. (1999) Leptin opposes insulin's effects on fatty acid partitioning in muscles isolated from obese ob/ob mice. Am J Physiol 276:E913-21
Goldfine, I D; Maddux, B A; Youngren, J F et al. (1998) Membrane glycoprotein PC-1 and insulin resistance. Mol Cell Biochem 182:177-84
Jones, J P; Tapscott, E B; Olson, A L et al. (1998) Regulation of glucose transporters GLUT-4 and GLUT-1 gene transcription in denervated skeletal muscle. J Appl Physiol 84:1661-6
Jones, J P; Roberts, B R; Tapscott, E B et al. (1997) Transcriptional regulation of hexokinase II in denervated rat skeletal muscle. Biochem Biophys Res Commun 238:53-5

Showing the most recent 10 out of 42 publications