My research interests focus on studying the mechanisms of inherited muscle and cardiovascular diseases. My interests in genetic muscle disease results in part from my previous training, but also because a genetic disease gives a researcher a handle to create a genetic model organism for which to study the disease mechanisms. Therefore, we utilize the power of genetic manipulation in cellular and animal models to study muscle function and in new ways, including combining muscle physiological measures with live cell imaging techniques to provide insights into muscle cell signalling and normal physiology, understand the contributions of important disease genes to normal muscle function, and identify causal disease mechanisms for therapy development. .
In addition to my laboratory, I serve as director of the Physiology Phenotyping Core which provides an array of phenotyping measures in animal models. The core is primarily focused on developing and providing state of the art measurements of cardiovascular and muscle phenotypes, providing surgical models of disease, and performing preclinical studies for testing therapies. If you have a grant or project that would benefit from the expertise of a core to phenotype your animal models, we would love to work with you.
My laboratory is currently interested in the molecular mechanisms of inherited muscular dystrophies. Muscular dystrophies are characterized by severe progressive muscle weakness, loss of ambulation and early death due to cardiac or respiratory failure. We specifically are interested in how genetic loss of function of dystroglycan and the associated dystrophin-glycoprotein complex results in muscle degeneration and weakness, and cardiomyopathy. A second area of interest is a second class of muscular dystrophies where the causative mechanism appears to be defective muscle membrane repair. Our research focuses on understanding why dystrophic muscles are susceptible to injury, what are the molecular pathways activated by injury leading to either activation of muscle membrane repair or degeneration, and additional roles of the dystrophin glycoprotein complex in muscle cell matrix interactions and mechanosignalling. The main approaches we use include : 1) genetic and pharmacologic manipulation of isolated muscle and cardiac cells from mouse models or human iPS cells 2) whole organ and whole animal cardiac and muscle physiology measurements in gene targeted and transgenic mouse models 3) live cell microscopy approaches to study cellular signalling and cell repair pathways to study disease mechanisms and identify potential therapeutic targets.
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.
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. 2013, 15;22(4):757-68.
McDade JR and Michele DE. Membrane damage induced vesicle-vesicle fusion of dysferlin containing vesicles in muscle cells requires microtubules and kinesin. Hum Mol Genetics, 23(7):1677-86, 2014.
McDade JR, Archanbeau AJ, Michele DE. Rapid actin cytoskeleton dependent membrane recruitment of plasma membrane derived dysferline at wounds is critical for muscle membrane repair. FASEB J. 28: 3660-70, 2014.