Elucidating Skeletal Muscle Satellite Cell:Microvessel Interactions in Diabetic Muscle

项目摘要 骨骼肌功能障碍显著导致2型糖尿病（T2 D）的许多后遗症。虽然 大多数针对描述糖尿病骨骼肌功能障碍的机制研究集中在 对于单细胞类型，更谨慎的是研究连接不同类型细胞的机制相互作用。为 例如，体内骨骼肌稳态的维持是骨骼肌和肌肉之间的协调相互作用。 生肌细胞和脉管系统。来自肌病肌肉的卫星细胞已经被证明具有减少的 影响血管生成，因此推测来自糖尿病肌肉的卫星细胞也具有 维持血管功能的能力减弱。对卫星间协调相互作用的理解 细胞和脉管系统需要了解调节卫星细胞介导的 对血管生成的影响本申请的总体目标是阐明卫星细胞介导的 导致糖尿病骨骼肌功能障碍的机制。核心假设是卫星细胞 来源于糖尿病肌肉的外泌体表现出其外泌体的变化，表现为 促进血管生成。为实现本项目的总体目标， 三个具体目标：（1）确定卫星细胞依赖的机制，有助于受损的血管生成 （2）阐明SIRT 1在糖尿病骨骼肌中介导卫星细胞依赖性机制的作用 （3）确定糖尿病患者卫星细胞依赖性活动减少的机制。 缺血再灌注（I/R）损伤后的肌肉。这三个独立但相关的具体目标的结果 将是确定控制卫星细胞影响血管生成能力的机制， 糖尿病肌肉，包括损伤后修复期间。

PROJECT SUMMARY Skeletal muscle dysfunction contributes significantly to the many sequelae of Type 2 Diabetes (T2D). Although the majority of mechanistic studies directed towards describing diabetic skeletal muscle dysfunction focus on a single cell type, it is more prudent to investigate the mechanistic interaction linking different types of cells. For example, the maintenance of skeletal muscle homeostasis in vivo is a coordinated interaction between the myogenic cells and the vasculature. Satellite cells from myopathic muscle have been shown to have a diminished effect on angiogenesis, so it is reasonable to speculate that satellite cells from diabetic muscle also have a weakened ability to maintain vessel function. An understanding of the coordinated interaction between satellite cells and the vasculature requires an understanding of the mechanisms that regulate satellite cell-mediated effects on angiogenesis. The overall objective of this application is to elucidate the satellite-cell mediated mechanisms that contribute to diabetic skeletal muscle dysfunction. The central hypothesis is that satellite cells derived from diabetic muscle exhibit changes in their exosomes that are manifested as an impaired ability to promote angiogenesis. The completion of the overall objective for this project will be accomplished by pursuing three specific aims: (1) Identify the satellite cell-dependent mechanisms that contribute to impaired angiogenesis in diabetic muscle; (2) Elucidate the role of SIRT1 in mediating satellite cell-dependent mechanisms in diabetic muscle; and, (3) Determine the mechanisms that cause diminished satellite cell-dependent activity in diabetic muscle after ischemia-reperfusion (I/R) injury. The outcome of these three separate, but related, specific aims will be the determination of the mechanisms that control the ability of satellite cells to affect angiogenesis in diabetic muscle, including during repair after injury.