Molecular mechanism of unloading-mediated insulin resistance

长时间卧床、瘫痪或太空飞行时的骨骼肌减负荷可导致衰弱的骨骼肌萎缩。肌肉质量减少的特征是蛋白质合成减少和蛋白质降解增加。目前，还没有治疗方法来逆转萎缩的进展。在这里，我们展示了Cbl-b，泛素连接酶家族的环型成员，在骨骼肌萎缩中是必不可少的。Cbl-b体内表达可导致大鼠胫前肌明显萎缩。相比之下，Cbl-b缺陷小鼠对尾部悬吊卸载过程中引起的肌肉萎缩和功能障碍具有抵抗力。在尾部悬吊或失重时，Cbl-b与骨骼肌生长因子信号中间体IRS-1相互作用并因此降解。因此，Cbl-b的激活似乎是萎缩的肌肉组织对IGF/胰岛素刺激的生长因子不敏感的基础，也可能是在肌肉萎缩过程中观察到的蛋白质合成总体下降的原因。这些数据表明，Cbl-b可能是一种新的靶点，用于在各种肌肉萎缩疾病中保护肌肉质量和功能的治疗方法的发展。

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.