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.
Highlights
Much research in the muscle field has been devoted to understanding myogenesis, muscle regeneration, and myofiber function (Bassel-Duby and Olson, 2006; Comai and Tajbakhsh, 2014; Potthoff and Olson, 2007; Schiaffino et al, 2013; Yin et al, 2013), there has been a growing recognition of the importance of maintenance of muscle mass in adulthood
We and others have shown that the splicing factors Rbfox1 and Rbfox2, which are highly conserved from C. elegans to humans (Gallagher et al, 2011; Jin et al, 2003; Kuroyanagi et al, 2007; Venables et al, 2012), are required for muscle differentiation and function (Pedrotti et al, 2015; Runfola et al, 2015; Singh et al, 2014); but, Rbfox factors have never been studied in adult skeletal muscle
Deletion of Rbfox1 and Rbfox2 in Adult Mice Causes Rapid, Severe Muscle Loss To determine the role of Rbfox splicing factors in mature adult myofibers, we induced knockout of Rbfox1, Rbfox2, or both in 7-week-old mice using a tetracycline-inducible and skeletal muscle-specific Cre line (Rao and Monks, 2009)
Summary
Much research in the muscle field has been devoted to understanding myogenesis, muscle regeneration, and myofiber function (Bassel-Duby and Olson, 2006; Comai and Tajbakhsh, 2014; Potthoff and Olson, 2007; Schiaffino et al, 2013; Yin et al, 2013), there has been a growing recognition of the importance of maintenance of muscle mass in adulthood. Muscle tissue faces special challenges: it must generate considerable force on demand and is continually exposed to mechanical, temperature, and oxidative stresses. Maintaining homeostasis under such conditions requires tight regulation of protein synthesis and turnover (Bell et al, 2016); failure of proteostasis occurs in many muscle diseases (Lecker et al, 2006; Nishino et al., 2000; Richard et al, 1995; Sandri et al, 2013), as well as the more general conditions of sarcopenia and cachexia (Bowen et al, 2015). We and others have shown that the splicing factors Rbfox and Rbfox, which are highly conserved from C. elegans to humans (Gallagher et al, 2011; Jin et al, 2003; Kuroyanagi et al, 2007; Venables et al, 2012), are required for muscle differentiation and function (Pedrotti et al, 2015; Runfola et al, 2015; Singh et al, 2014); but, Rbfox factors have never been studied in adult skeletal muscle
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