A Role for the Transcriptional Coregulator RIP140 in the Control of Muscle Endurance Fitness [CUTnRUN_Ac_flat]

Poor skeletal muscle fitness contributes to many chronic disease states including obesity, heart failure, primary muscle disorders, and age-related sarcopenia. Receptor Interacting Protein 140 (RIP140) is a striated muscle-enriched nuclear receptor co-regulator. To investigate the role of RIP140 in skeletal muscle, striated muscle-specific RIP140-deficient (strNrip1-/-) mice were generated and characterized. strNrip1-/- mice display a remarkable endurance performance phenotype based on endurance treadmill performance, VO2max testing, and functional assessment of isolated muscle. RNA-sequence analysis of glycolytic fast-twitch muscle from the strNrip1-/- mice identified a broad array of differentially upregulated metabolic and structural muscle genes involved in muscle endurance fitness pathways including mitochondrial biogenesis and respiration, fatty acid oxidation, triglyceride dynamics, muscle fiber type, angiogenesis, and neuromuscular junction (NMJ) remodeling. Assessment of the structural correlates of these processes confirmed the function of RIP140 as placing a “brake” on the transcriptional network controlling these key muscle endurance fitness processes. Integration of the RNA sequence results with CUT&RUN analysis of strNrip1-/- myotubes identified direct RIP140 targets including genes involved in fatty acid metabolism and NMJ biogenesis. We conclude that RIP140 serves as a physiological “rheostat” for a broad network of genes involved in skeletal muscle fitness.