Centro de Investigaación del Cáncer, CSIC-University of Salamanca, 37007, Salamanca, Spain.
Instituto de Biología Molecular y Celular del Cáncer, CSIC-University of Salamanca, 37007, Salamanca, Spain.
Nat Commun. 2020 Nov 16;11(1):5808. doi: 10.1038/s41467-020-19489-z.
Skeletal muscle promotes metabolic balance by regulating glucose uptake and the stimulation of multiple interorgan crosstalk. We show here that the catalytic activity of Vav2, a Rho GTPase activator, modulates the signaling output of the IGF1- and insulin-stimulated phosphatidylinositol 3-kinase pathway in that tissue. Consistent with this, mice bearing a Vav2 protein with decreased catalytic activity exhibit reduced muscle mass, lack of proper insulin responsiveness and, at much later times, a metabolic syndrome-like condition. Conversely, mice expressing a catalytically hyperactive Vav2 develop muscle hypertrophy and increased insulin responsiveness. Of note, while hypoactive Vav2 predisposes to, hyperactive Vav2 protects against high fat diet-induced metabolic imbalance. These data unveil a regulatory layer affecting the signaling output of insulin family factors in muscle.
骨骼肌通过调节葡萄糖摄取和刺激多个器官间的串扰来促进代谢平衡。我们在这里表明，Rho GTP 酶激活剂 Vav2 的催化活性调节了 IGF1 和胰岛素刺激的磷脂酰肌醇 3-激酶通路在该组织中的信号输出。与此一致的是，携带催化活性降低的 Vav2 蛋白的小鼠表现出肌肉质量减少、缺乏适当的胰岛素反应性，并且在稍后的时间出现代谢综合征样情况。相反，表达催化超活性 Vav2 的小鼠则发生肌肉肥大和胰岛素反应性增加。值得注意的是，虽然低活性 Vav2 易患，高活性 Vav2 则可预防高脂肪饮食引起的代谢失衡。这些数据揭示了一个调节层，影响肌肉中胰岛素家族因子的信号输出。
