Background: Mechanical unloading of the failing human heart induces profound cardiac changes resulting in the reversal of a distorted structure and function. In this process, cardiomyocytes break down unneeded proteins and replace those with new ones. The specificity of protein degradation via the ubiquitin proteasome system is regulated by ubiquitin ligases. Over-expressing the ubiquitin ligase MAFbx/Atrogin-1 in the heart inhibits the development of cardiac hypertrophy, but the role of MAFbx/Atrogin-1 in the unloaded heart is not known. Methods and results: Mechanical unloading, by heterotopic transplantation, decreased heart weight and cardiomyocyte cross-sectional area in wild type mouse hearts. Unexpectedly, MAFbx/Atrogin-1-/- hearts hypertrophied after transplantation (n=8-10). Proteasome activity and markers of autophagy were increased to the same extent in WT and MAFbx/Atrogin-1-/- hearts after transplantation (unloading). Calcineurin, a regulator of cardiac hypertrophy, was only upregulated in MAFbx/Atrogin-1-/- transplanted hearts, while the mTOR pathway was similarly activated in unloaded WT and MAFbx/Atrogin-1-/- hearts. MAFbx/Atrogin-1-/- cardiomyocytes exhibited increased calcineurin protein expression, NFAT transcriptional activity, and protein synthesis rates, while inhibition of calcineurin normalized NFAT activity and protein synthesis. Lastly, mechanical unloading of failing human hearts with a left ventricular assist device (n=18) also increased MAFbx/Atrogin-1 protein levels and expression of NFAT regulated genes. Conclusions: MAFbx/Atrogin-1 is required for atrophic remodeling of the heart. During unloading, MAFbx/Atrogin-1 represses calcineurin-induced cardiac hypertrophy. Therefore, MAFbx/Atrogin-1 not only regulates protein degradation, but also reduces protein synthesis, exerting a dual role in regulating cardiac mass.
- Atrophic remodeling
- Heart assist device
- Heterotopic heart transplantation
- Protein turnover
ASJC Scopus subject areas
- Molecular Biology
- Cardiology and Cardiovascular Medicine