Abstract 1266: An Essential Role for Muscle Ring Finger-1 (MuRF1) Expression in the Reversal of Cardiac Hypertrophy In Vivo
Muscle Ring Finger-1 (MuRF1) is a muscle-specific protein initially discovered for its essential role in mediating skeletal muscle atrophy. Our previous studies identified that MuRF1 interacted with sarcomeric proteins (e.g. cardiac troponin I) and degraded them in a proteasome-dependent manner. To extend those findings, we examined the importance of MuRF1 in reversing cardiac hypertrophy using a model of hypertrophy regression. MuRF1 −/− or wild-type (WT) mice underwent a modified trans-aortic constriction, whereby a reversible tie was placed. Weekly echocardiography was performed for 4 weeks, after which time the aortic band was released non-invasively. Mice were then echoed for an additional 4 weeks to follow the resulting regression of cardiac hypertrophy. As previously reported, MuRF1 −/− mice exhibited an exaggerated hypertrophic response following 4 weeks of banding compared to WT controls (1.53 +/− 0.04 vs. 1.31 +/− 0.08 mm anterior wall in diastole, N=10/group, P<0.05) (Circ Res. 100(4):456 –9, 2007). While cardiac hypertrophy regressed 100% in WT mice 1 week after the aortic band was removed (cardiac mass reduced from 131.7 +/− 19.8 mg to 78.4 +/− 9.5 mg), MuRF1 −/− mice regressed only ~30% from maximal hypertrophy (cardiac mass reduced 145.6 +/− 6.6 mg to 126.6 +/− 4.0 mg) four weeks after debanding. This paralleled changes in MuRF1 −/− anterior wall thickness (reduced ~37% from maximal hypertrophy) and posterior wall thickness (reduced ~40% from maximal hypertrophy) during the same time frame. To demonstrate the relevance of MuRF1 in human cardiac muscle mass regression, we assayed MuRF1 in cardiac tissue from patients undergoing placement of a left ventricular assist device (LVAD) for transition to transplant at placement and after subsequent cardiac transplant. Cardiac mass decreased by 17% after LVAD placement (as determined by echocardiography). By Western blot, MuRF1 levels significantly increased ~54% after the induction of atrophy (N=4, P<0.001). Taken together, these studies demonstrate for the first time that MuRF1 expression is increased in human heart after cardiac mass regression, and that MuRF1 is necessary for the regression of cardiac hypertrophy in vivo.