The proper association of muscle fibers with laminin in the extracellular matrix is essential for normal muscle function. The alpha7Beta1 integrin and the dystrophin-glycoprotein complex both bind laminin and appear to be complementary linkage systems between fibers and the extracellular matrix. Congenital and acquired defects in the dystrophin-glycoprotein complex underlie the pathology associated with Duchenne and other muscular dystrophies, as well as cardiomyopathies. Mutations in the human alpha7 gene cause an additional myopathy. We recently discovered that enhanced expression of the alpha7 integrin mediated linkage system can compensate for the absence of the dystrophin-glycoprotein complex. Dystrophin/utrophin null mice develop an acute muscular dystrophy and die prematurely. Enhanced expression of the alpha7 integrin inhibits the development of muscular dystrophy and restores longevity to these animals. We propose to expand on this result and determine the level of alpha7Beta1 integrin that best prevents development of skeletal muscle pathology in these animals and whether transgene expression in the heart and smooth muscle can prevent cardiovascular disease. We will also analyze whether enhanced expression of the alpha7 integrin in the heart reduces development of cardiomyopathy associated with enterovirus-induced cleavage of dystrophin. Additional skeletal muscle and cardiomyopathies result from other defects in the dystrophin-glycoprotein linkage system. We will use transgenic animals that over-express the alpha7Beta1 integrin in different genetic backgrounds to determine whether the integrin can prevent these myopathies. Whereas mutations in the sarcoglycan genes perturb the dystrophin-glycoprotein transmembrane linkage system and cause cardiomyopathy and muscular dystrophy, we will determine whether over-expression of the alpha7 integrin can inhibit the development of muscle disease in sarcoglycan deficient mice. Likewise, we will assess whether enhanced integrin expression will ameliorate alpha2-laminin congenital muscular dystrophy. Lastly, experiments are proposed that aim at understanding the mechanism by which enhanced integrin expression inhibits development of muscle pathology. This research will reveal whether increasing alpha7 integrin levels in humans may be worth pursuing in the future as treatments for Duchenne and other muscular dystrophies and cardiomyopathies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG014632-06
Application #
6533779
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Williams, John
Project Start
1997-01-24
Project End
2006-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
6
Fiscal Year
2002
Total Cost
$304,305
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Okada, Hideshi; Lai, N Chin; Kawaraguchi, Yoshitaka et al. (2013) Integrins protect cardiomyocytes from ischemia/reperfusion injury. J Clin Invest 123:4294-308
Liu, Jianming; Milner, Derek J; Boppart, Marni D et al. (2012) ?1D chain increases ?7?1 integrin and laminin and protects against sarcolemmal damage in mdx mice. Hum Mol Genet 21:1592-603
Boppart, Marni D; Burkin, Dean J; Kaufman, Stephen J (2011) Activation of AKT signaling promotes cell growth and survival in ?7?1 integrin-mediated alleviation of muscular dystrophy. Biochim Biophys Acta 1812:439-46
Gurpur, Praveen B; Liu, Jianming; Burkin, Dean J et al. (2009) Valproic acid activates the PI3K/Akt/mTOR pathway in muscle and ameliorates pathology in a mouse model of Duchenne muscular dystrophy. Am J Pathol 174:999-1008
Liu, Jianming; Burkin, Dean J; Kaufman, Stephen J (2008) Increasing alpha 7 beta 1-integrin promotes muscle cell proliferation, adhesion, and resistance to apoptosis without changing gene expression. Am J Physiol Cell Physiol 294:C627-40
Boppart, Marni D; Volker, Sonja E; Alexander, Nicole et al. (2008) Exercise promotes alpha7 integrin gene transcription and protection of skeletal muscle. Am J Physiol Regul Integr Comp Physiol 295:R1623-30
Liu, Jianming; Gurpur, Praveen B; Kaufman, Stephen J (2008) Genetically determined proteolytic cleavage modulates alpha7beta1 integrin function. J Biol Chem 283:35668-78
Hanft, Laurin M; Bogan, Daniel J; Mayer, Ulrike et al. (2007) Cytoplasmic gamma-actin expression in diverse animal models of muscular dystrophy. Neuromuscul Disord 17:569-74
Chao, Jun-Tzu; Martinez-Lemus, Luis A; Kaufman, Stephen J et al. (2006) Modulation of alpha7-integrin-mediated adhesion and expression by platelet-derived growth factor in vascular smooth muscle cells. Am J Physiol Cell Physiol 290:C972-80
Boppart, Marni D; Burkin, Dean J; Kaufman, Stephen J (2006) Alpha7beta1-integrin regulates mechanotransduction and prevents skeletal muscle injury. Am J Physiol Cell Physiol 290:C1660-5

Showing the most recent 10 out of 16 publications