Elucidating Skeletal Muscle Satellite Cell:Microvessel Interactions in Diabetic Muscle

项目总结 骨骼肌功能障碍是2型糖尿病(T2D)许多后遗症的重要原因。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 对于单个细胞类型，更谨慎的做法是研究连接不同类型细胞的机制相互作用。为 例如，体内骨骼肌内稳态的维持是一种协调的相互作用 肌源性细胞和血管系统。来自肌病肌肉的卫星细胞已经被证明具有减少的 对血管生成的影响，因此有理由推测来自糖尿病肌肉的卫星细胞也有 维持血管功能的能力减弱。对卫星间协调相互作用的认识 细胞和血管系统需要了解调节卫星细胞介导的机制。 对血管生成的影响。这项应用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。中心假设是卫星细胞 来自糖尿病肌肉的来源在其外体中表现出变化，表现为能力受损 促进血管生成。本项目总体目标的完成将通过以下工作来实现 三个具体目标：(1)确定导致血管生成受损的卫星细胞依赖机制 (2)阐明SIRT1在糖尿病卫星细胞依赖机制中的作用 肌肉；以及，(3)确定糖尿病患者卫星细胞依赖活动减弱的机制。 缺血再灌注(I/R)损伤后肌肉。这三个独立但又相互关联的具体目标的结果 将是对控制卫星细胞影响血管生成能力的机制的确定 糖尿病肌肉，包括在损伤后修复期间。

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.