Muscular Dystrophy
Currently, our work with Duchenne muscular dystrophy is focused on the therapeutic potential of the PGC-1α pathway. We have advanced from early gene transfer experiments demonstrating the efficacy of PGC-1α over-expression to our current work focused on identifying compounds that can activate this pathway. We found that the orally available and safe PGC-1α activator, quercetin, protected dystrophic hearts and cardiac function throughout a year-long supplementation study but provided only transient benefits to skeletal muscle. We are working to determine why this differential effect was found so that appropriate changes can be made to future studies as we prepare for a clinical trial.
We also recognized that limitations in existing dystrophinopathy animal models are hindering therapy development. To address this critical need we began the creation of a novel transgenic porcine dystrophinopathy model. During the course of this investigation we joined a team that had recently discovered a spontaneously occurring pig dystrophinopathy model. We are in the process of performing the initial characterizations of these models with the hope that they can be inserted into the preclinical pipeline. Use of these large animal models would allow the testing of drugs in human sized models with many physiological systems more similar to humans than either the currently available mouse or dog models.
Heat Stress
We are also interested in how heat stress negatively impacts skeletal muscle physiology and growth. It is well recognized that heat stress results in a number of pathological conditions including heat rash, illness, stroke, and even heat-related death in humans. In agricultural settings heat stress leads to health and welfare concerns for the animal and negative economic impacts for the producer by way of impaired growth efficiency, among others. Aside from cooling there is little in the way of countermeasures to treat heat stress organisms. A requisite step in the development of effective therapies is an appreciation of pathologic changes caused by heat stress. Given this, we are particularly interested in improving our mechanistic understanding of pathological changes in skeletal muscle caused by prolonged heat stress. At the whole muscle level during and following heat stress muscle size is smaller than thermo neutral controls. Furthermore, application of in utero heat stress causes offspring to have less lean tissue. This is in stark contrast to brief exposure to heat, which results in enhanced muscle growth and even blunts atrophy caused by unweighting or disuse. Hence, we are also interested in discerning molecular events that distinguish therapeutic hypothermia from pathological heat stress. Gaining this mechanistic understanding of heat stress is necessary for the development of therapies to protect human patients from injury as well as maintain efficient meat production in an agricultural setting.