Areas of Interest
The Michele laboratory is focused on the mechanisms of muscular dystrophy associated with mutations in the transmembrane dystrophin-glycoprotein complex. In addition to skeletal muscle disease, patients with muscular dystrophy often develop and succumb to cardiomyopathy. We are exploring disease mechanisms in vivo using gene targeted mouse models as well as human patient samples. To complement these approaches, cardiac muscle cells and isolated muscle tissues are used to study the cellular mechanisms of how loss of function of the dystrophin glycoprotein complex affects the mechanical stability and force transmission of muscle.
One of the features of muscular dystrophy is profound muscle weakness and muscle fatigue. While muscle degeneration is clearly a significant contributor to muscle weakness, muscular dystrophy patients also experience abnormal blood flow to their muscles. When one exercises, muscle blood flow increases during exercise in the face of the high sympathetic nervous system activity due to a process called functional sympatholysis. During exercise, active muscle releases local vasodilator mediators, such as nitric oxide which locally vasodilate the vessels supplying muscle with blood flow. Little is known about how nitric oxide synthase is regulated by muscle contractions and if and how this regulation is disrupted in muscular dystrophies. Our work is to uncover these mechanisms to identify important targets for therapy.
Muscles from muscular dystrophy patients and mouse models with mutations in the dystrophin glycoprotein complex also show marked sensitivity to contraction induced injury. This is in part thought to be due to a structural role for the dystrophin-glycoprotein complex in stabilizing the sarcolemma during mechanical stress. Muscle has developed a remarkable ability to repair the sarcolemma after injury within seconds, a process that is mediated in part by the protein dysferlin. Dysferlin is mutated in patients with LGMD 2B and Myoshi myopathy. We have developed methodologies to watch the membrane repair pathway activation in real time using live cell microscopy and transgenic mice expressing GFP reporter constructs that show the localization and orientation of dysferlin in the muscle fiber membrane. We are utilizing these mice to study the mechanisms of how the membrane repair pathway is regulating following experimental and physiological muscle injury.
- Ph.D. University of Michigan, 2000
- Kabaeva Z, Meekhof KE, Michele DE. Sarcolemma instability during mechanical activity in Largemyd cardiac myocytes with loss of dystroglycan extracellular matrix receptor function. Hum Mol Genet. 2011 Sep 1;20(17):3346-55. PMC3153301.
- Gumerson JD, Davis CS, Kabaeva ZT, Hayes JM, Brooks SV, Michele DE. Muscle-specific expression of LARGE restores neuromuscular transmission deficits in dystrophic LARGE(myd) mice. Hum Mol Genet. 2013 Feb 15;22(4):757-68. PMC3554202.
- McDade JR, Michele DE. Membrane damage-induced vesicle-vesicle fusion of dysferlin-containing vesicles in muscle cells requires microtubules and kinesin. Hum Mol Genet. 2014 Apr 1;23(7):1677-86. PMC3943514.
- McDade JR, Archambeau A, Michele DE. Rapid actin-cytoskeleton-dependent recruitment of plasma membrane-derived dysferlin at wounds is critical for muscle membrane repair. FASEB J. 2014 Aug;28(8):3660-70. PMC4101652.
- Garbincius JF, Michele DE. Dystrophin-glycoprotein complex regulates muscle nitric oxide production through mechanoregulation of AMPK signaling. Proc Natl Acad Sci U S A. 2015 Nov 3;112(44):13663-8. PMC4640723.
- Campbell MD, Witcher M, Gopal A, Michele DE. Dilated cardiomyopathy mutations in δ-sarcoglycan exert a dominant-negative effect on cardiac myocyte mechanical stability. Am J Physiol Heart Circ Physiol. 2016 May 1;310(9):H1140-50. PMC4867387.
- Eisen B, Ben Jehuda R, Cuttitta AJ, Mekies LN, Shemer Y, Baskin P, Reiter I, Willi L, Freimark D, Gherghiceanu M, Monserrat L, Scherr M, Hilfiker-Kleiner D, Arad M, Michele DE, Binah O. Electrophysiological abnormalities in induced pluripotent stem cell-derived cardiomyocytes generated from Duchenne muscular dystrophy patients. J Cell Mol Med. 2019 Mar;23(3):2125-2135. PMC6378185.
- Garbincius JF, Merz LE, Cuttitta AJ, Bayne KV, Schrade S, Armstead EA, Converso-Baran KL, Whitesall SE, D'Alecy LG, Michele DE. Enhanced dimethylarginine degradation improves coronary flow reserve and exercise tolerance in Duchenne muscular dystrophy carrier mice. Am J Physiol Heart Circ Physiol. 2020 Sep 1;319(3):H582-H603. PMC7509273.
- McDade JR, Naylor MT, Michele DE. Sarcolemma wounding activates dynamin-dependent endocytosis in striated muscle. FEBS J. 2020 Sep 7. doi: 10.1111/febs.15556. Epub ahead of print. PMID: 32893434.