萎缩骨骼肌自噬增强可能诱导胰岛素抵抗

Insulin resistance of skeletal muscle is a key pathogenesis of type 2 diabetes mellitus. Hypodynamics of skeletal muscle is one of main inducers of insulin resistance. Spaceflight-induced atrophy of anti-gravity skeletal muscles in astronauts has also shown insulin resistance, but the underlying mechanisms of insulin resistance in atrophic muscles are unclear. Our lab has got some evidence that the enhanced autophagy in atrophic skeletal muscles may be associated with the inhibition in plasmalemma translocation of glucose transporter 4 (GLUT4) vescles. The tail-suspended rat model will be used to unload skeletal muscles in hindlimb of rats and to exert atrophy in anti-gravity skeletal muscles. This study is (1) to observe the changes of autophagic flux in atrophic skeletal muscles and to demonstrate that the enhanced autophagy results in insulin resistanc of atrophic skeletal muscles; (2) to screen out the vesicle-associated membrane protein (VAMP) isoforms which bind with GLUT4 vescles and autophagosomes; (3) to elucidate that the increased autophagosomes in atrophic skeletal muscle may competitively combine VAMP with GLUT4 vescles; and (4) to demonstrate that lack of sufficient VAMP in atrophic skeletal muscles may retard the plasmalemma translocation of GLUT4 and further induces insulin resistance. These studies should provide valuable information for the molecular mechanisms of insulin resistance in the disused atrophy of skeletal muscles. Our long-term goal is to make the efficient countermeasement to prevent astronauts from insulin resistance in atrophic skeletal muscles during and after long-term spaceflight.

骨骼肌胰岛素抵抗是2型糖尿病的关键性病理改变，低运动负荷则是其主要诱因之一。航天失重致航天员抗重力骨骼肌萎缩，呈现胰岛素抵抗，其机制尚不清楚。本实验室发现萎缩骨骼肌自噬增加可能抑制葡萄糖转运体4(GLUT4)囊泡向细胞膜转位，因此，利用尾部悬吊大鼠后肢抗重力骨骼肌萎缩模型，拟开展下列研究：(1)观测萎缩骨骼肌自噬通量的变化，证明萎缩骨骼肌自噬增强是导致其胰岛素抵抗的主要原因。(2)筛选出骨骼肌纤维中既与GLUT4囊泡共定位，又与自噬体共定位的囊泡相关膜蛋白(VAMP)异构体。(3)探明萎缩骨骼肌因自噬通量增加时，自噬体与GLUT4囊泡竞争性结合VAMP；(4)阐明萎缩骨骼肌由于VAMP相对不足导致GLUT4转位减少，进而引起胰岛素抵抗。这些结果有利于阐明废用性萎缩骨骼肌胰岛素抵抗的机制；并在长期航天飞行活动中，制定防止航天员萎缩骨骼肌胰岛素抵抗的有效措施。

低运动负荷是诱发骨骼肌胰岛素抵抗最终导致2型糖尿病的主要因素之一。航天失重致航天员抗重力骨骼肌萎缩，呈现胰岛素抵抗，其机制尚不清楚。本实验室发现萎缩骨骼肌自噬增加可能抑制葡萄糖转运体4(GLUT4)囊泡向细胞膜转位，因此，利用尾部悬吊大鼠后肢抗重力骨骼肌萎缩模型，在整体、骨骼肌组织与培养细胞水平进行观测，获得的主要研究结果有：(1)发现萎缩骨骼肌自噬通量明显增强，并证明萎缩骨骼肌自噬增强是导致其胰岛素抵抗的主要原因。(2)在骨骼肌纤维，筛选出既与GLUT4囊泡共定位，又与自噬体共定位的囊泡相关膜蛋白为VAMP2。(3)在模拟失重大鼠比目鱼肌，证明萎缩骨骼肌因自噬通量增加时，自噬体与GLUT4囊泡竞争性结合VAMP2，并在培养C2C12肌管中进一步确认此结果；(4)阐明萎缩骨骼肌由于VAMP2相对不足导致GLUT4转位减少，进而引起胰岛素抵抗。这些结果基本阐明了废用性萎缩骨骼肌胰岛素抵抗的新机制；并在长期航天飞行活动中，为制定防止航天员萎缩骨骼肌胰岛素抵抗的有效措施提供了实验数据。