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Cell Rep. 2018 Jul 3;24(1):197-208. doi: 10.1016/j.celrep.2018.06.017.

Rbfox-Splicing Factors Maintain Skeletal Muscle Mass by Regulating Calpain3 and Proteostasis.

Author information

1
Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: ravis@bcm.edu.
2
Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
3
Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
4
Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular & Cell Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: tcooper@bcm.edu.

Abstract

Maintenance of skeletal muscle mass requires a dynamic balance between protein synthesis and tightly controlled protein degradation by the calpain, autophagy-lysosome, and ubiquitin-proteasome systems (proteostasis). Several sensing and gene-regulatory mechanisms act together to maintain this balance in response to changing conditions. 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. Rbfox deletion did not cause a reduction in global protein synthesis, but it led to altered splicing of hundreds of gene transcripts, including capn3, which produced an active form of calpain3 protease. Rbfox knockout also led to a reduction in autophagy flux, likely producing a compensatory increase in general protein degradation by the proteasome. Our results indicate that the Rbfox-splicing factors are essential for the maintenance of skeletal muscle mass and proteostasis.

KEYWORDS:

Rbfox; alternative splicing; autophagy; calpain; muscle biology; proteasome; proteostasis

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