2008 Awarded Grant

Monte S. Willis, MD, PhD

The Role of MuRF1 in MyBP-c Turnover and Its Effects on Cardiac Energy Metabolism in Familial Hypertrophic Cardiomyopathy
University of North Carolina, Chapel Hill, NC
2008 Amount Awarded – $50,000

Familial hypertrophic cardiomyopathies (FHC) are the most common underlying cause of sudden death in children and young adults, which result from mutations primarily in proteins responsible for heart contraction. It has been identified that the cardiac specific protein MuRF1 (Muscle Ring Finger-1), mediates the degradation of one of these proteins, the cardiac Myosin Binding Protein-C (cMyBP-c). Since cMyBP-c is the most commonly mutated protein in patients with FHC, and cMyBP-c is degraded very rapidly by heart cells in these patients, this study proposes that MuRF1 may be a key regulator of this degradation as a mechanism to clear damaged proteins. Moreover, it has been identified that MURF1 regulates the turnover of proteins that transport energy (ATP) throughout the cell, and that MuRF1 inhibits increases in muscle size (cardiomyocyte hypertrophy). Therefore, the assumption is that MuRF1 is a unifying mechanism for the major underlying defects in FHC. The intent of this study is to show that in the presence of mutant cMyBP-c, MuRF1 preferentially recognizes and degrades these proteins because it identifies them as defective. When the heart mainly creates defective cMyBP-c (as in FHC), cardiac MuRF1 spends all its time clearing the mutant protein. The cost of this constant clearance is that MuRF1 is not available to regulate the heart size, or energy transport, which would explain the enlarged (hypertrophic) hearts in FHC, and the energy deficits identified in FHC patients. By identifying that MuRF1 mediates these multiple defects in FHCs, targeting and enhancing MuRF1 activity may specifically improve outcomes in patients with FHC.

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