Mitochondriopathy of Chronically Ischemic Muscle

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DESCRIPTION (provided by applicant): Application objective: The proposal describes a five-year program of basic science research coupled with closely mentored laboratory guidance, coursework and seminars that will significantly broaden my scientific education and help me become an independent clinician/scientist in an academic medical center. Research: Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis affecting approximately 8.4 million people in the US, most of them elderly. The current treatment options for patients with PAD are limited to revascularization operations (100,000 per year) or amputations (50,000 per year), while effective non-operative treatment options are very few. The manifestations of PAD, including claudication and gangrene, result from decreased energy levels within the affected tissue. This reduced energy state appears to result not only from reduced blood flow through diseased arteries, but also faulty ATP production from dysfunctional mitochondria. We have earlier demonstrated the presence of mitochondrial dysfunction in both human and mouse chronically ischemic skeletal muscle. Preliminary results from our murine model of hindlimb ischemia suggest that the defects originate from decreased activity of electron transport chain complexes III and IV. Furthermore, our results point to an association between the mitochondrial defects and oxidative stress. The goal of this proposal is to utilize our murine model to further delineate the electron transport chain defects and to correlate mitochondrial defects with muscle dysfunction and oxidative damage. The identified defects may provide an important therapeutic target for treating PAD patients, especially those with unreconstructible disease. We hypothesize that chronic skeletal muscle ischemia is associated with alterations in the activity and content of the electron transport chain complexes III and IV, and that these defects correlate with muscle contractile dysfunction and evidence of oxidative stress. Four focused specific aims are proposed: Aim 1: Identify and quantify defects in the function of electron transport chain complexes I through IV in mitochondria from ischemic muscle. Aim 2: Identify the subunit defects in the dysfunctional electron transport chain complexes. Aim 3: Correlate mitochondrial dysfunction with muscle contractile properties. Aim 4: Correlate mitochondrial dysfunction with oxidative damage in the ischemic skeletal muscle.