Abstract 3210: The Ubiquitin Ligase Atrogin-1, but Not MuRF-1, is Required for Atrophic Remodeling of the Heart
As the heart remodels in response to a load change, cardiomyocytes break down unnecessary or damaged proteins and use the resulting amino acids for the synthesis of new proteins and/or energy provision. We have previously reported that components in the ubiquitin proteasome system (UPS) are upregulated during cardiac remodeling. The UPS degrades proteins in a specific manner by tagging them with ubiquitin for degradation by ubiquitin ligases. Two muscle specific ubiquitin ligases, Atrogin-1 and MuRF-1, are required for skeletal muscle atrophy. Their over-expression inhibits the development of cardiac hypertrophy. However, their role the heart’s response to mechanical unloading has never been investigated. We tested the hypothesis that Atrogin-1 and MuRF-1 are required for atrophic remodeling of the heart. Wild type (WT), Atrogin-1 knockout, MuRF-1 knockout, and double knockout mice (8 –10 weeks old, n=5– 8 each group) were subjected to mechanical unloading by heterotopic heart transplantation. Seven days after surgery cardiomyocyte size as well as changes in transcript and protein levels were measured. Heart weight and myocyte area were significantly reduced in transplanted WT hearts. Conventional markers of atrophic remodeling, such as MHC isoform switching, were also detected in the transplanted WT hearts. Surprisingly, in transplanted hearts lacking MuRF-1, hearts atrophied to a similar degree as WT hearts. In contrast, transplanted hearts lacking Atrogin-1 significantly hypertrophied (20% increase in heart weight). Double-knockout transplanted hearts also hypertrophied, but to a lesser extent (10% increase in heart weight). In conclusion, the absence of either Atrogin-1 alone or of both ligases disrupts the atrophic remodeling process. Atrogin-1 appears to be most important in regulating atrophic remodeling in the heterotopically transplanted heart. The data also suggest that ubiquitin ligases are regulators of cardiac mass irrespective of loading conditions.