Dan Michele, Ph.D.

One of the outstanding things about working in academia is the opportunity to work with people from all different backgrounds, from all over the country, and from all over the world. Our diversity is something to learn about, learn from, and celebrate. I can be a more supportive mentor by learning about people's background, and how that has shaped who they are now, and is driving their long term goals.

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.