Tenotomy-induced muscle atrophy is sex-specific and independent of NFκB

Abstract

The nuclear factor-{kappa}B (NF{kappa}B) pathway is a major thoroughfare for skeletal muscle atrophy and is driven by diverse stimuli. Targeted inhibition of NF{kappa}B through its canonical mediator IKK{beta} effectively mitigates loss of muscle mass across many conditions, from denervation to unloading to cancer. In this study, we used gain- and loss-of-function mouse models to examine the role of NF{kappa}B in muscle atrophy following rotator cuff tenotomy - a model of chronic rotator cuff tear. IKK{beta} was knocked down or constitutively activated in muscle-specific inducible transgenic mice to elicit a 2-fold gain or loss of NF{kappa}B signaling. Surprisingly, neither knockdown of IKK{beta} nor overexpression of caIKK{beta} significantly altered the loss of muscle mass following tenotomy. This finding was consistent across measures of architectural adaptation (fiber cross-sectional area, fiber length, fiber number), tissue pathology (fibrosis and fatty infiltration) and intracellular signaling (ubiquitin-proteasome, autophagy). Intriguingly, late-stage tenotomy-induced atrophy was exacerbated in male mice compared to female mice. This sex specificity was driven by ongoing decreases in fiber cross-sectional area, which paralleled the accumulation of large autophagic vesicles in male, but not female muscle. These findings suggest that tenotomy-induced atrophy is not dependent on NF{kappa}B and instead may be regulated by autophagy in a sex-specific manner.