Skeletal muscle fitness is a key determinant of systemic metabolism and overall health. Poor muscle fitness contributes to the morbidity associated with disease states such as obesity and diabetes, heart failure, primary muscle diseases, and age-related cachexia. Receptor Interacting Protein 140 (RIP140) is a nuclear receptor co-regulator that is known to repress genes involved in oxidative metabolism and is relatively enriched in fast-twitch muscle. To investigate the role of RIP140 in skeletal muscle, striated (heart and skeletal) muscle-specific RIP140-/- (strNrip1-/-) mice were generated and characterized. strNrip1-/- mice display a remarkable endurance performance phenotype. Specifically, strNrip1-/- mice run significantly longer on an endurance treadmill regimen and exhibit a greater VO2max at baseline and following exercise training compared to control mice. Respiratory Exchange Ratio (RER) is maintained at a significantly lower level during exercise in str-RIP140 KO mice compared to wild-type controls, indicative of increased capacity for fatty acid oxidation. Skeletal muscle-specific RIP140-/- (skmNrip1-/-) mice phenocopied the strNrip1-/- mice. Bulk RNA-sequencing analysis of fast-twitch muscle identified differentially upregulated genes involved in an array of endurance training responses including mitochondrial energy transduction, triglyceride turnover, the oxidative fiber program, angiogenesis, and neuromuscular junction (NMJ) remodeling. Assessment of the structural correlates of these processes confirmed the function of RIP140 as a ”brake” on the transcriptional network controlling muscle endurance. For example, strNrip1-/- mice display a shift to more oxidative fibers in fast-twitch muscle, increased mitochondria number and lipid droplets, and an increase in motor endplate area of the neuromuscular junction. CUT&RUN sequencing analysis from strNrip1-/- myotubes revealed RIP140 gene targets involved in fatty acid metabolism, angiogenesis and NMJ function. Taken together, we conclude that RIP140 serves as a transcriptional co-repressor of a network of genes involved in maintaining skeletal muscle endurance. Accordingly, RIP140 should be considered as a target for novel metabolic therapies aimed at cardiac and skeletal muscle diseases.