A role for the transcriptional coregulator RIP140 in the control of muscle endurance fitness.

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 coregulator known to suppress mitochondrial oxidative capacity. To investigate the role of RIP140 in skeletal muscle, striated muscle-specific RIP140-deficient (strNrip1-/-) mice were generated and characterized. strNrip1-/- mice displayed an enhanced endurance performance phenotype. RNA-sequence (RNA-seq) analysis of glycolytic fast-twitch muscle from strNrip1-/- mice identified a broad array of differentially upregulated metabolic and structural muscle genes known to be induced by endurance training, including pathways involved in mitochondrial biogenesis and respiration, fatty acid oxidation, slow muscle fiber type, and angiogenesis. In addition, muscle RIP140 deficiency induced expansive neuromuscular junction (NMJ) remodeling. Integration of RNA-seq results with CUT&RUN analysis of strNrip1-/- myotubes identified Wnt16 as a candidate effector for the NMJ biogenesis in RIP140-deficient skeletal myotubes. We conclude that RIP140 serves as a physiological "rheostat" for a broad coordinated network of metabolic and structural genes involved in skeletal muscle fitness.