The Role of Cytokeratins in Skeletal Muscle Injury

本研究的目的是增加对肌肉损伤、治疗和恢复机制的理解。我的假设是细胞角蛋白K8和K19在骨骼肌肌膜的组织和功能中起着不可或缺的作用。我将使用功能、形态学和分子生物学方法通过3个特定目的来验证这一假设：1)a：将肌肉损伤模型应用于小鼠，并将随后的收缩功能与患有已知肌营养不良症的小鼠（mdx小鼠）进行比较；比较mdx和野生型（wt）单纤维的力与全肌肉结果和转染表达功能性肌营养不良蛋白的病毒的mdx纤维的力，2)确定缺乏细胞角蛋白K8或K19的肌肉是否营养不良和/或更容易受到损伤，以及通过腺病毒转染将缺失的亚基替换到肌纤维中是否纠正了营养不良或改变了对损伤的易感性，3)了解K8或K19的过表达是否会导致肌病。一些肌肉萎缩症的组织病理学与损伤引起的肌肉变化有明显的相似之处。提出的研究旨在阐明一些共同的细胞和分子机制。

The goal of this research is to increase understanding of the mechanisms underlying muscle injury, treatment, and recovery. My hypothesis is that cytokeretins K8 & K19 play an integral part in the organization and function of the sarcolemma of skeletal muscle. I will use functional, morphological, and molecular biological approaches to test this hypothesis through 3 specific aims: 1) a: To adapt a model of muscle injury to mice and compare subsequent contractile function to mice with a known dystrophinopathy (mdx mice), b: to compare forces of mdx and wild-type (wt) single-fibers to the whole-muscle findings and to mdx fibers transfected with a virus expressing a functional dystrophin, 2) To determine whether muscles lacking cytokeratin K8 or K19 are dystrophic and/or more susceptible to injury, and if replacement of the missing subunit into muscle fibers by adenoviral transfection corrects the dystrophy or alters susceptibility to injury, 3) To learn if overexpression of K8 or K19 results in myopathy. There are marked similarities in the histopathology of some muscular dystrophies and the changes in muscle induced by injury. The proposed research is designed to elucidate some of the shared cellular and molecular mechanisms.