Molecular mechanism of unloading-mediated insulin resistance

在长时间卧床休息、瘫痪或太空飞行期间，骨骼肌卸载可导致衰弱性骨骼肌萎缩。肌肉质量减少的特点是蛋白质合成减少和蛋白质降解增加。目前，还没有治疗方法可以逆转萎缩的进展。在这里，我们表明Cbl-b，一个环型成员的泛素连接酶家族，是骨骼肌萎缩所必需的。体内表达Cbl-b可引起大鼠胫骨前肌明显萎缩。相比之下，Cbl-b缺陷小鼠对尾巴悬架卸载时引起的肌肉萎缩和功能障碍有抵抗力。在悬尾或零重力时，Cbl-b与骨骼肌生长因子信号传导中间体IRS-1相互作用，从而降解。因此，Cbl-b激活似乎是萎缩肌肉组织对IGF/胰岛素的生长因子刺激的难耐性的基础，也可能是肌肉萎缩期间观察到的蛋白质合成总体减少的原因。这些数据表明，Cbl-b可能是开发治疗药物的新靶点，目的是在各种肌肉萎缩疾病期间保持肌肉质量和功能。

Skeletal muscle unloading during prolonged bed rest, paralysis, or spaceflight can result in debilitating skeletal muscle atrophy. Reduced muscle mass is characterized by a combination of decreased protein synthesis and increased protein degradation. Currently, there is no treatment to reverse the progression of atrophy. Here we show that Cbl-b, a RING-type member of the ubiquitin ligase family, is essential for skeletal muscle atrophy. Expression of Cbl-b in vivo induces significant atrophy in rat tibialis anterior muscle. In contrast, Cbl-b deficient mice are resistant to muscle atrophy and dysfunction induced during unloading by tail suspension. Upon tail suspension or zero gravity, Cbl-b interacts with and thereby degrades the skeletal muscle growth factor signaling intermediate IRS-1. Thus, Cbl-b activation appears to underlie the refractoriness of atrophic muscle tissue to growth factor stimulation by IGF/insulin and likely accounts for the overall decrease in protein synthesis observed during muscle wasting. These data suggest that Cbl-b may be a novel target for the development of therapeutics aimed at the preservation of muscle mass and function during a variety of muscle wasting diseases.