Abstract 13959: A Role for Striated Muscle Nuclear Receptor Co-Regulator RIP140 ( Nrip1 ) in the Control of Endurance Fitness

Abstract

During the development of heart failure (HF), the capacity for myocardial fatty acid oxidation (FAO) and oxidative phosphorylation is reduced, leading to an energy-starved state. Similar metabolic derangements occur in skeletal muscle during HF and with physical inactivity associated with chronic disease states. Receptor Interacting Protein 140 (RIP140) is a nuclear receptor co-regulator that has been shown to repress the transcription of genes involved in mitochondrial energy transduction in highly metabolic tissues. We recently demonstrated that striated muscle-specific RIP140 KO mice (str-RIP140 -/- ) were protected against the development of HF and had an adaptive form of cardiac hypertrophy (PMID: 36927960). To assess the impact of RIP140 deficiency on skeletal muscle function, we conducted physiological and genomic interrogation of str-RIP140 -/- mice. We found that the str-RIP140 -/- mice display an endurance performance phenotype. Specifically, str-RIP140 -/- mice run significantly longer on an endurance treadmill regimen (str-RIP140 -/- = 118.0 min, WT= 73.38 min; p= <0.0001) with increased VO 2max compared to controls (str-RIP140 -/- = 9779 ml/kg/hr, WT= 7748 ml/kg/hr; p= <0.0001). Respiratory Exchange Ratio (RER) was maintained at a decreased level during exercise in str-RIP140 -/- mice vs controls, indicative of increased utilization and capacity for FAO. The response of str-RIP140 -/- mice to endurance exercise training was also assessed. str-RIP140 -/- mice achieved a greater VO 2max following 8 weeks of training compared to control trained mice (str-RIP140 -/- = 9589 ml/kg/hr, WT= 8366 ml/kg/hr; p= 0.002). RNA-sequence analysis comparing RIP140 -/- and control fast-twitch muscle (EDL) prior to and following exercise training identified differentially upregulated genes involved in an array of pathways activated with endurance training including mitochondrial FAO, triglyceride turnover, the slow-twitch fiber program, angiogenesis, and components of the neuromuscular junction. We conclude that RIP140 serves as a co-repressor of a network of genes involved in skeletal muscle endurance. These results suggest that RIP140 could prove to be a target for novel metabolic therapies aimed at cardiac and skeletal muscle diseases.