Identifying Critical Molecular Targets to Suppress Age-Related Muscle Fiber Loss

描述(由申请人提供)：骨骼肌团块进行性消瘦(骨质疏松症)是一种广泛传播的、与年龄相关的病理状态，发现于现代老年人群。肌肉质量的丧失伴随着进行性的肌肉无力，恶化了老年人的生活质量，与死亡率和发病率上升不谋而合，估计医疗成本高达数十亿美元。与年龄相关的肌肉质量损失反映在肌肉结构的微观变化上，其中单个肌肉纤维的丢失是特征事件之一。年龄相关纤维丢失(ARFL)和肌肉萎缩的本质和分子机制显然很复杂，目前还不清楚。因此，迫切需要确定影响衰老肌肉中ARFL发生率的广泛的分子靶点。这些信息将成为开发预防和治疗方法以遏制与年龄相关的肌肉萎缩的关键。我的长期目标是确定延长肌肉健康寿命的遗传因素和分子机制。这里的目标是识别一系列肌肉基因，这些基因的活性可能与增强对ARFL的抵抗力有关。我的中心假设是，通过改变肌肉转录组，特别是通过上调编码结构肌肉蛋白的基因的表达，可以实现细胞自主地增强肌肉对ARFL的抵抗力。这个拟议项目的预期结果是扩大基因和基因相互作用的清单，这些基因和基因相互作用对于提供对与年龄相关的纤维退化和丢失的耐受性至关重要。这些结果将对人类健康产生积极影响，因为它们将为开发诊断和治疗方法提供新的候选者，以检测和消除导致骨质疏松症发生的分子过程。

DESCRIPTION (provided by applicant): The progressive wasting of skeletal muscle mass (sarcopenia) is a wide-spread, age-related pathological condition found in the modern elderly populations. The loss of muscle mass, paralleled by progressive muscular weakness, deteriorates the quality of living among the elderly, coincides with increased mortality and morbidity rates, and has an estimated healthcare cost of billions of dollars. Age-related muscle mass loss is reflected by microscopic changes in the muscle architecture, where loss of individual muscle fibers is one of the characteristic events. The nature and molecular mechanisms underlying age-related fiber loss (ARFL) and muscle wasting are apparently complex and currently not well understood. Thus, there is an urgent need for identification of a broad range of molecular targets that influence the rate of ARFL in aging muscles. This information will become critical in developing prophylactic and therapeutic approaches to curb age-related muscle wasting. My long-term goal is to identify genetic factors and molecular mechanisms that prolong healthy lifespan of muscles. The objectives here are to identify a range of muscle genes whose activity could be associated with increased resistance against ARFL. My central hypothesis is that greater muscle resistance to ARFL can be achieved cell-autonomously, through changes in muscle transcriptome, specifically by up- regulating expression of genes encoding structural muscle proteins. The expected outcome of this proposed project is an expansion in the list of genes and gene interactions essential to provide tolerance against age- related fiber degeneration and loss. These results will have a positive impact on human health as they will supply novel candidates for developing diagnostic and therapeutic approaches to detect and abrogate molecular processes leading to development of sarcopenia.