Muscle‐Specific Ubiquitin Ligase MuRF1 Regulates Myocardial Autophagic Flux in vivo

Abstract

The ubiquitin‐proteasome and autophagy systems are complementary protein degradation pathways that play a critical role in protein quality control and protein turnover in cardiomyocytes. The specificity of the UPS is carried out by ubiquitin ligases (E3), including the muscle‐specific Muscle Ring Finger‐1 (MuRF1). Mounting evidence suggests that there is interplay between the UPS and autophagic pathways; however they are not yet well understood in the heart. To identify MuRF1′s regulation of autophagic flux, MuRF1‐/‐ and sibling MuRF1+/+ controls were treated with Bafilomycin A1 and hearts harvested for western analysis of LC3BI/II expression. MuRF1‐/‐ animals showed significantly less autophagic flux (72% reduction vs. MuRF1+/+, P<0.01). The p62/SWSQSTM1 ubiquitin‐binding scaffold that colocalized with ubiquitinated protein aggregates were decreased in the absence of MuRF1 and significantly increased when MuRF1 expression increased in vivo (MuRF1 Tg+ hearts) by western analysis. Taken together, these findings suggest MuRF1 expression regulates myocardial autophagy in vivo and may link convergence of the UPS and autophagy system. Since increasing cardiomyocyte autophagic flux can support the heart's resiliency (ischemia reperfusion injury) or impair its ability to maintain function (pressure overload induced‐cardiac hypertrophy), its regulation can be finely tuned in a disease‐specific manner. Understanding MuRF1′s regulation of autophagy provides useful insight for the development of therapies targeting autophagy in heart disease.