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

描述（由申请人提供）：骨骼肌质量的进行性消耗（肌肉减少症）是在现代老年人群中广泛存在的与年龄相关的病理状况。肌肉质量的减少，同时伴有进行性肌肉无力，使老年人的生活质量恶化，死亡率和发病率上升，估计造成数十亿美元的医疗费用。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损失是特征事件之一。年龄相关性纤维损失（ARFL）和肌肉萎缩的本质和分子机制显然是复杂的，目前还没有得到很好的理解。因此，迫切需要确定影响老化肌肉中ARFL速率的广泛分子靶点。这一信息对于开发预防和治疗方法来抑制与年龄相关的肌肉萎缩至关重要。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。这里的目的是确定一系列肌肉基因，其活性可能与对ARFL的抗性增加有关。我的中心假设是，更大的肌肉对ARFL的抵抗可以通过肌肉转录组的变化，特别是通过上调编码结构肌肉蛋白的基因的表达来实现细胞自主。这项计划的预期结果是扩大基因和基因相互作用的清单，提供对年龄相关的纤维变性和损失的耐受性。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物，以检测和消除导致肌肉减少症发展的分子过程。

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.