Rbfox-Splicing Factors Maintain Skeletal Muscle Mass by Regulating Calpain3 and Proteostasis. Cell Rep 2018 Jul 03;24(1):197-208
Date
07/05/2018Pubmed ID
29972780Pubmed Central ID
PMC6070147DOI
10.1016/j.celrep.2018.06.017Scopus ID
2-s2.0-85048989217 (requires institutional sign-in at Scopus site) 40 CitationsAbstract
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.
Author List
Singh RK, Kolonin AM, Fiorotto ML, Cooper TAMESH terms used to index this publication - Major topics in bold
AnimalsAutophagy
Calpain
Energy Metabolism
Gene Deletion
Glucose
Mice, Inbred C57BL
Mice, Knockout
Muscle Proteins
Muscle Strength
Muscle, Skeletal
Physical Endurance
Proteostasis
RNA Splicing Factors
Transcriptome
