Research Areas
The Michele 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.
FUNCTION OF THE DYSTROPHIN GLYCOPROTEIN COMPLEX IN MUSCULAR DYSTROPHY
MECHANOSENSATION AND THE REGULATION OF LOCAL MUSCLE BLOOD FLOW
MECHANISMS OF MUSCLE MEMBRANE REPAIR
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 in vivo using spontaneous mutant, traditional and conditional targeted mouse models as well as human patient samples. We are also using a variety of cellular models including cardiac muscle cells and isolated muscle tissues to study the 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. A major contributor to functional sympatholysis is that exercising muscle releases 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 complex in stabilizing the sarcolemma during mechanical stress. Muscle has developed a remarkable ability to repair the sarcolemma after injury, 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 realtime 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.