Cardiac MuRF1 regulates PPAR‐α agonist‐induced spontaneous cardiac hypertrophy in vivo

Abstract

The ubiquitin proteasome system is a protein degradation system mediated in part by the muscle ring finger‐1 (MuRF1) ubiquitin ligase. MuRF1 has been shown to play an important role in cardiac hypertrophy. MuRF1 also targets and inhibits PPAR‐α activity, with MuRF1‐/‐ hearts showing increased PPAR‐α activity in vivo. The unique duality of MuRF1′s regulation of cardiac hypertrophy and PPAR‐α's activity led us to determine the in vivo effect of MuRF1 on PPAR‐α signaling. This was done by challenging them with fenofibrate, a PPAR‐α agonist. MuRF1‐/‐ and age matched sibling MuRF1+/+ controls received standard chow or fenofibrate chow (0.5% w/w). Echocardiography determined cardiac function at 3 and 8 weeks, followed by cardiac tissue analysis by RT‐PCR, histology, and electron microscopy. Fenofibrate induced a time dependent increase in cardiac hypertrophy, evidenced by significant (P<0.05) increases in cardiac wall thickness and cardiomyocyte cross sectional area in MuRF1‐/‐ mice (25% increase vs MuRF1+/+). Pathological hypertrophy genes beta‐myosin heavy chain, smooth muscle alpha‐actin, and brain natriuretic peptide were also increased in fenofibrate fed MuRF1‐/‐ mice. Additionally, fenofibrate fed MuRF1‐/‐ mice exhibited increased lipid filled vesicles in and around mitochondria as well as increased mitochondrial fallout compared to fenofibrate fed MuRF+/+ mice. These findings suggest that cardiac hypertrophy associated with PPAR‐α agonist fed MuRF1‐/‐ mice appear to be pathological in nature. These data also show, for the first time, the interplay between MuRF1, PPAR‐α, and hypertrophic cardiomyopathy pathways, indicating a unique role for PPAR‐α in cardiac hypertrophy.