MUSCLE RESPONSE TO STRESS IN CANINE MUSCULAR DYSTROPHY

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This project will provide the applicant with the research skills required to develop and assess rehabilitation treatments that enhance function for patients with muscular dystrophy. Throughout a doctoral program in physiology, a major portion of effort will be devoted to a mentored research project which will examine the relationship between mechanical stress and muscle fiber injury in a canine homolog of Duchenne muscular dystrophy. The central hypothesis of this research is that fiber damage in dystrophin-deficient muscle results, in part, from an exaggerated response to mechanical stress incurred during contraction. Furthermore, muscles involved in lengthening contractions are subject to greater stress than other muscles, and are preferentially injured. The central hypothesis will be tested in selected hindlimb muscles of dystrophic dogs by evaluating cellular and physiological features of muscle fiber response to varying levels of imposed stress. Although the mdx mouse is more readily available and a more commonly used experimental model, the dystrophic dog expresses clinical features analogous to humans with Duchenne muscular dystrophy. Aim 1 will correlate muscle membrane damage with myofiber necrosis: Aim 2 will compare regenerative features in muscles involved in lengthening contractions with muscles involved in shortening contractions: Aim 3 will determine if a lower threshold to stress-induced injury exists in dystrophic fibers compared to controls: and Aim 4 will determine if reducing mechanical stress during growth will eliminate or decrease the exaggerated fiber necrosis and remodeling seen in the adult gastrocnemius muscle. It is anticipated that findings will improve the understanding of how dystrophic muscle responds to physical stress resulting in improved treatment for patients with Duchenne muscular dystrophy.