Rbfox splicing factors maintain skeletal muscle mass by regulating calpain3 and proteostasis

ABSTRACT Alternative splicing promotes proteomic diversity important for cellular differentiation and cell fate determination. Here, we show that deletion of the highly conserved Rbfox1 and Rbfox2 alternative splicing regulators in adult mouse skeletal muscle causes rapid, severe loss of muscle mass. Homeostasis of skeletal muscle tissue requires a dynamic balance between protein synthesis and degradation (proteostasis) but the mechanisms that regulate this balance are not well understood. Rbfox deletion did not cause reduced global protein synthesis, but resulted in reduced autophagy flux and altered splicing of hundreds of transcripts including Capn3, which produced an active form of calpain3 protease. The results indicate Rbfox proteins regulate proteostasis in skeletal muscle tissue by control of calpain and autophagy-lysosome pathways. Highlights Proteostasis in adult skeletal muscle is post-transcriptionally regulated, in part by alternative splicing via Rbfox1/2 Rbfox1/2 regulate hundreds of targets in skeletal muscle, including Calpn3, to maintain muscle mass in adult mice Autophagy flux is markedly decreased in muscle lacking Rbfox1/2 As for neurons, altered proteostasis is detrimental to adult muscle