Receptor Interacting Protein 140 (Nrip1) Controls Cardiac Fuel Metabolism and Function [RNA-seq]

During development of heart failure, capacity for cardiomyocyte fatty acid oxidation (FAO) and ATP production is progressively diminished contributing to pathologic cardiac hypertrophy and contractile dysfunction. Receptor interacting protein 140 (RIP140; Nrip1) has been shown to function as a transcriptional co-repressor of oxidative metabolism. Here we show that mice lacking RIP140 in striated muscle (strRIP140-/-) have increased expression of a broad array of involved in a broad array of mitochondrial energy metabolism and contractile function in heart and skeletal muscle. strRIP140-/- mice were resistant to the development of pressure overload-induced cardiac hypertrophy, and cardiomyocyte-specific RIP140 deficient (csRIP140-/-) mice were defended against development of heart failure caused by pressure overload combined with myocardial infarction. Genomic enhancers activated by RIP140 deficiency in cardiomyocytes were enriched in binding motifs for transcriptional regulators of mitochondrial function (estrogen-related receptor) and cardiac contractile proteins (myocyte enhancer factor 2). Consistent with a role in the control of cardiac fuel metabolism, loss of RIP140 in heart resulted in augmented triacylglyceride turnover and FA utilization. We conclude that RIP140 functions as a suppressor of a transcriptional regulatory network that controls cardiac fuel metabolism and contractile function, representing a potential therapeutic target for heart failure. Overall design: Differential gene expression analysis of RNA-Seq data from cardiac ventricles of mice lacking RIP140 in striated muscle and control mice