Areas of Interest
My laboratory is interested in the molecular mechanisms of human diseases of skeletal and cardiac muscle. By understanding molecular mechanisms of relatively rare genetic disorders, we hope to shed light on common mechanisms that cause more common idiopathic or acquired forms of skeletal muscle and cardiac disease. Currently, we are focused on the mechanisms of muscular dystrophy associated with mutations in the transmembrane dystrophin-glycoprotein complex. There has been an explosion of genetic evidence indicating that the central protein in this complex, dystroglycan, is the key player in a number of muscular dystrophies. However, this is not due to primary mutations in dystroglycan itself, but mutations in enzymes that modify the function of dystroglycan as an extracellular matrix receptor. Patients with muscular dystrophy often develop and succumb to cardiomyopathy. The cellular mechanisms of dystroglycan modification and the resulting pathways leading to muscular dystrophy and cardiomyopathy are currently unclear. We are exploring these pathways using spontaneous mutant, traditional and conditional targeted mouse models as well as human patient samples. In addition, protein complexes containing some of the components of the dystrophin-glycoprotein complex in muscle are expressed throughout the body. Human patients and mouse models with defects in dystroglycan function have altered neuronal migration, synaptic function, peripheral nerve structure and function, eye development and function, and neuromuscular junction formation. We are trying to identify some of the functional ligands of dystroglycan, compensating receptors, and molecules associated with the dystroglycan complex in non-muscle tissues that are necessary for these various non-muscle phenotypes seen in human patients, and whether or not these same molecules have any functional role in skeletal and cardiac muscle disease.
Michele DE, Albayya FP, Metzger JM. Direct, convergent hypersensitivity of Ca2+ activated force generation produced by hypertrophic cardiomyopathy mutant tropomyosins in adult cardiac myocytes. Nature Medicine 5(12): 1413-1417, 1999.
Michele DE, Barresi R, Kanagawa M, Saito F, Cohn RD, Satz JS, Dollar J, Nishino I, Kelley RI, Somer H, Straub V, Mathews KD, Moore SA, and Campbell KP. Post-translational disruption of dystroglycan-ligand interactions in congenital muscular dystrophies. Nature. 418: 417-422, 2002
Yasuda S*, Townsend D*, Michele DE, Favre EG, Day SM, Metzger JM. Dystrophic heart failure blocked by membrane sealant poloxamer. Nature. 436(7053):1025-9, 2005
Kabaeva Z, Zhao M, Michele DE. Blebbistatin extends culture life of adult mouse cardiac myocytes and allows efficient and stable transgene expression. Am J Physiol Heart Circ Physiol. 2008 Apr;294(4):H1667-74.
Michele DE*, Kabaeva Z, Davis SL, Weiss RM, Campbell KP. Dystroglycan matrix receptor function in cardiac myocytes is important in limiting activity induced myocardial damage. Circulation Research 105:984-993, 2009. *Corresponding Author. Featured on Cover.
Salazar JJ, Michele DE, Brooks SV. Inhibition of calpain prevents muscle weakness and disruption of sarcomere structure during hindlimb suspension. J Appl Physiol. 108:120-1277, 2010.
Gumerson JD, Davis C, Faulkner JA, Michele DE. Protection from contraction induced injury in slow twitch muscle with disruption of dystroglycan function. Am J Physiol Cell Physiol. 299:C1430-40, 2010.
Ramaswamy KS, Palmer ML , vanderMeulen JM, Renoux A, Kostrominova TY, Michele DE* , Faulkner JA*. Lateral transmission of force is impaired in skeletal muscles of dystrophic mice and very old rats. Journal of Physiology. 589: 1195-208, 2011 *co-corresponding authors.
Kabaeva Z, Meehof K, Michele DE. Sarcolemma instability during mechanical activity in Largemyd cardiac myocytes with loss of dystroglycan extracellular matrix receptor function. Hum Mol Genetics 20:3346-3355, 2011.
Gumerson JD, Davis C, Kabaeva ZT, Hayes JM, Brooks SV, Michele DE. Muscle-specific expression of LARGE restores neuromuscular transmission deficits in dystrophic LARGEmyd mice. Hum Mol Genetics. 22(4):757-68, 2013
- Ph.D. University of Michigan, 2000