Discovery of heart-derived myokines mediating the response to exercise stress via PGC-1a

PROJECT SUMMARY This proposal seeks to support the career development of Dr. Sumeet Khetarpal MD, PhD, a physician-scientist, cardiology fellow and incoming Instructor at Massachusetts General Hospital (MGH). Dr. Khetarpal seeks five years of mentored research support for training in exercise, cardiac metabolism and proteomics to catalyze his career development as an independent physician-scientist in cardio-metabolic diseases. These diseases are major causes of death and healthcare costs in the world. While many treatments exist, disease burden remains high, prompting the need for new approaches to therapy and prevention. Exercise reduces the onset of and morbidity from many cardiovascular diseases including heart failure. The molecular mediators of exercise that confer beneficial effects have been poorly defined particularly in the heart. In muscle and adipose tissue, exercise promotes secretion of proteins that regulate energy balance. A key regulator of this process is the exercise- induced transcription factor PGC-1α, which governs mitochondrial responses to energy stress. The heart's adaptation to exercise involves increasing mitochondrial function. However, the role of the heart as a secretory organ is poorly understood. This proposal tests the hypothesis that heart-secreted proteins (myokines) contribute importantly to the heart's adaptation to exercise and prevention of heart failure. Initial studies will focus on the contribution of maladaptive myokines to the development of cardiac atrophy in a mouse model of exercise- induced heart failure lacking PGC-1α. Subsequent studies will test the ability of one newly identified PGC-1α- dependent myokine to mitigate cardiac dysfunction in a model of heart failure. A third effort will identify novel heart-derived myokines from exercise-trained mice through proteomics of heart extracellular fluid. Collectively this work will provide an understanding of how endurance exercise modulates heart protein secretion and generate datasets (the cardiac “secretome” of exercise). This will provide a fundamental platform for the applicant's transition to independence. Dr. Khetarpal will greatly benefit from primary mentorship by Dr. Bruce Spiegelman at Harvard Medical School (HMS), a world-leader in molecular metabolism and discovery of novel metabolically active myokines. Key intellectual co-mentorship in cardiac molecular adaptations to exercise will be provided by Dr. Anthony Rosenzweig at the University of Michigan. Dr. Khetarpal will also be advised by a team of cardiovascular physician-scientists at HMS (Dr. Patrick Ellinor and Dr. Jason Roh of MGH and Dr. Aarti Asnani at Beth Israel). Dr. Khetarpal also has rich support from key HMS collaborators on proteomics (Dr. Steve Gygi) and lipid metabolism (Dr. Jorge Plutzky) and a deep commitment from MGH and his primary mentor Dr. Spiegelman at HMS. Through the outlined mentorship and investigation, Dr. Khetarpal will complement his prior training in human genetics and lipid metabolism to new domains of proteomic screens, mitochondrial metabolism and cardiac physiology. This will provide an incredibly rich foundation for a successful career as an independent academic physician-scientist working to reduce cardio-metabolic disease morbidity through molecular discovery.