Metabolism, Skeletal Muscle, Cardiac Disease, Exercise

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Candidate: The candidate, John P. Konhilas, Ph.D., is a research associate endeavoring to broaden his extensive training in cardiovascular physiology to encompass additional biological systems and timely molecular techniques. Dr. Konhilas1 immediate career goal is to acquire the research and professional skills necessary for achieving his long-term goal of developing an independent, extramurally-funded translational research program focusing on the regulation of skeletal muscle characteristics during cardiac disease states and exercise in animals as it relates to human disease. The proposed K01 development plan will provide Dr. Konhilas with the additional experience and training to achieve this goal. Career Development Plan: Training activities during the award period include, (1) acquiring new and refining present research skills, (2) structured activities including coursework in scientific integrity, biostatistics, and attendance/presentation at journal clubs, scientific meetings, and mentoring interactions. Environment: Dr. Konhilas has assembled a team of mentors to provide guidance in every facet of the proposal. The sponsor, Dr. Leslie Leinwand, is a well-established extramurallyfunded scientist and a proven mentor. She has provided a productive and nurturing research environment necessaryfor career development. Research: The hypothesis to be tested states that the oxidative capacity of skeletal muscle is reduced during cardiac disease states and can be recovered by exercise training. To examine the role of critical metabolic mediators in this process, lipoprotein lipase or peroxisome proliferator-activated receptor alpha will be genetically disrupted in skeletal muscle by systemic administration of adeno-associated viral (AAV) vectors at specific times during cardiac disease progression and exercise. In all animals, the skeletal muscles will be analyzed for MyHC content, muscle fiber size, and oxidative capacity. Relevance: Severe skeletal muscle weaknessand fatigue upon exertion are major clinical features that occur in patients with congestive heart failure (CHF). The exercise intolerance can be reversed in CHF patients with aerobic exercise independent of central cardiac effects. Therefore, it is of major clinical significance that the mechanistic link be determined between cardiac disease, the associated abnormalities in skeletal muscle, and exercise. This proposal will examine specific regulators of this disease process and evaluate their role during disease and exercise recovery.