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

## TL;DR

RIP140, a protein in muscle cells, limits muscle endurance and fitness by suppressing genes involved in energy production and muscle structure.

## Contribution

The study identifies RIP140 as a key regulator of muscle endurance and exercise response through transcriptional control.

## Key findings

- RIP140-deficient mice showed improved endurance and upregulated genes related to mitochondrial function and muscle fitness.
- Muscle RIP140 deficiency caused neuromuscular junction remodeling and identified Wnt16 as a potential effector.
- RIP140 acts as a 'rheostat' for metabolic and structural genes in skeletal muscle.

## Abstract

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.

Daniel Kelly and team show that the protein RIP140 serves a key role in modulating the transcriptional control of skeletal muscle endurance fitness and the exercise training response.