Centro Interdisciplinario de Neurociencia de Valparaíso. Facultad de Ciencias, Universidad de Valparaíso, Valparaíso, Chile.
Programa de Farmacología Molecular y Clinica, ICBM, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
Sci Rep. 2017 Jul 4;7(1):4580. doi: 10.1038/s41598-017-04418-w.
Dynamin-2 is a ubiquitously expressed GTP-ase that mediates membrane remodeling. Recent findings indicate that dynamin-2 also regulates actin dynamics. Mutations in dynamin-2 cause dominant centronuclear myopathy (CNM), a congenital myopathy characterized by progressive weakness and atrophy of skeletal muscles. However, the muscle-specific roles of dynamin-2 affected by these mutations remain elusive. Here we show that, in muscle cells, the GTP-ase activity of dynamin-2 is involved in de novo actin polymerization as well as in actin-mediated trafficking of the glucose transporter GLUT4. Expression of dynamin-2 constructs carrying CNM-linked mutations disrupted the formation of new actin filaments as well as the stimulus-induced translocation of GLUT4 to the plasma membrane. Similarly, mature muscle fibers isolated from heterozygous knock-in mice that harbor the dynamin-2 mutation p.R465W, an animal model of CNM, exhibited altered actin organization, reduced actin polymerization and impaired insulin-induced translocation of GLUT4 to the sarcolemma. Moreover, GLUT4 displayed aberrant perinuclear accumulation in biopsies from CNM patients carrying dynamin-2 mutations, further suggesting trafficking defects. These results suggest that dynamin-2 is a key regulator of actin dynamics and GLUT4 trafficking in muscle cells. Our findings also support a model in which impairment of actin-dependent trafficking contributes to the pathological mechanism in dynamin-2-associated CNM.
动力蛋白-2 是一种普遍表达的 GTP 酶，介导膜重塑。最近的研究结果表明，动力蛋白-2 还调节肌动蛋白动力学。动力蛋白-2 突变导致显性中心体肌病（CNM），这是一种以骨骼肌进行性无力和萎缩为特征的先天性肌病。然而，这些突变影响的动力蛋白-2 的肌肉特异性作用仍然难以捉摸。在这里，我们表明，在肌肉细胞中，动力蛋白-2 的 GTP 酶活性参与新的肌动蛋白聚合以及肌动蛋白介导的葡萄糖转运蛋白 GLUT4 的运输。携带 CNM 相关突变的动力蛋白-2 构建体的表达破坏了新肌动蛋白丝的形成以及 GLUT4 刺激诱导向质膜易位。同样，携带 dynamin-2 突变 p.R465W 的杂合 knock-in 小鼠分离的成熟肌纤维，该突变是 CNM 的动物模型，表现出肌动蛋白组织改变、肌动蛋白聚合减少和胰岛素诱导的 GLUT4 向肌膜易位受损。此外，在携带 dynamin-2 突变的 CNM 患者的活检中，GLUT4 表现出异常的核周聚集，进一步表明存在运输缺陷。这些结果表明，动力蛋白-2 是肌肉细胞中肌动蛋白动力学和 GLUT4 运输的关键调节剂。我们的研究结果还支持这样一种模型，即肌动蛋白依赖性运输的损害导致与 dynamin-2 相关的 CNM 的病理机制。
