Program in Physical Therapy, Washington University School of Medicine, St. Louis, United States.
Department of Orthopaedic Surgery, Washington University School of Medicine, St Louis, United States.
Elife. 2022 Dec 12;11:e82016. doi: 10.7554/eLife.82016.
The nuclear factor-κB (NFκB) pathway is a major thoroughfare for skeletal muscle atrophy and is driven by diverse stimuli. Targeted inhibition of NFκB through its canonical mediator IKKβ 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 NFκB in muscle atrophy following rotator cuff tenotomy - a model of chronic rotator cuff tear. IKKβ was knocked down or constitutively activated in muscle-specific inducible transgenic mice to elicit a twofold gain or loss of NFκB signaling. Surprisingly, neither knockdown of IKKβ nor overexpression of caIKKβ significantly altered the loss of muscle mass following tenotomy. This finding was consistent across measures of morphological 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 with 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 NFκB and instead may be regulated by autophagy in a sex-specific manner.
核因子-κB（NFκB）通路是骨骼肌萎缩的主要途径，受多种刺激驱动。通过其经典介质 IKKβ 靶向抑制 NFκB 可有效减轻多种情况下的肌肉质量损失，从去神经支配到卸载到癌症。在这项研究中，我们使用了 gain- 和 loss-of-function 小鼠模型来研究 NFκB 在肩袖 Tenotomy 后肌肉萎缩中的作用 - 一种慢性肩袖撕裂模型。在肌肉特异性诱导型转基因小鼠中敲低或组成型激活 IKKβ，以引发 NFκB 信号的两倍增益或损失。令人惊讶的是，敲低 IKKβ或过表达 caIKKβ都没有显着改变 Tenotomy 后肌肉质量的损失。这一发现与形态适应的各种测量结果一致（纤维横截面积、纤维长度、纤维数量）、组织病理学（纤维化和脂肪浸润）和细胞内信号（泛素-蛋白酶体、自噬）。有趣的是，与雌性小鼠相比，雄性小鼠晚期 Tenotomy 诱导的萎缩更为严重。这种性别特异性是由纤维横截面积的持续下降驱动的，这与雄性肌肉中大量自噬小体的积累相平行，但雌性肌肉中没有。这些发现表明，Tenotomy 诱导的萎缩不依赖于 NFκB，而是可能以性别特异性方式受到自噬的调节。
