Mechanosensory Signal Transduction in Aging Muscle

骨质疏松症是一种与年龄相关的骨骼肌质量减少和 可能导致身体残疾和丧失独立性。它是 假设骨质疏松症的影响可能延迟或在很大程度上 如果现有的肌肉组织可以被诱导肥大，就会被阻止。 尽管人们普遍认为肌肉的适应性会随着年龄的增长而下降， 一个根本的问题仍然没有解决：什么是分子基础 衰老肌肉的适应能力下降？在心脏 组织很明显，增加的负荷能够调节细胞 肥大。骨骼肌中是否存在类似的机制是 不知道。这项研究的总体目标是确定潜在的 独立或共享的细胞内信号通过其级联 肌肉负荷增加对成人和老年人基因表达的调节 骨骼肌。为了实现这一目标，成年人、中年人、 老年或衰老的Fisher 344 X Brown挪威(F1)大鼠将 在体外进行拉伸，激活将被确定。杂交F12代 之所以选择老鼠，是因为我们实验室的新数据 证明了年老的F1动物不能承受负荷 诱导性肌肉肥大。这个项目的假设是年龄 肌肉适应性的相关降低与 肌肉机械感觉信号转导。这项提议的目的是 目标1)。确定拉伸是否诱导MAPK家族的激活 与成人肌肉相比，成员在衰老的肌肉中变弱。目标2)。 为了确定肌肉拉伸是否增加了FAK的活性 成人和老年骨骼肌。这项工作对BASIC具有广泛的应用 以及生物医学和健康科学领域的应用领域。在 在基础科学层面上，这些研究将增加我们对 收缩组织在适应改变过程中可能使用的通路 加载条件。在更实用的层面上，这项研究将提供 将提供对调节骨骼肌的途径的洞察 肥大，并找出那些可能成为靶点的通路 预防患者肌肉萎缩的新治疗策略和 虚弱的老人。

Sarcopenia is an age associated reduction in skeletal muscle mass and may contribute to physical disability and loss of independence. It is hypothesized that the effects of sarcopenia could be delayed or largely prevented if existing musculature could be induced to hypertrophy. Although it is well accepted that muscle adaptability declines with aging, a fundamental issue remains unresolved: What is the molecular basis for the decreased ability of aged muscle to undergo adaptation? In cardiac tissue it is apparent that increased loading is able to mediate cellular hypertrophy. Whether a similar mechanism exists in skeletal muscle is not known. The overall goal of this study is to identify potential independent or shared intracellular signaling cascades through which increased muscle loading regulates gene expression in adult and aged skeletal muscle. To fulfill this goal, muscles from adult, middle aged, and aged or senescent Fisher 344 X Brown Norway (F1) rats will undergo stretch in vitro and activation will be determined. F12 hybrid rats were chosen because novel data from our laboratory has demonstrated that aged F1 animals are incapable of undergoing load induced muscle hypertrophy. The hypothesis for this project is that age associated decreases in muscle adaptation are related to a decrease in muscle mechanosensory signal transduction. The aims of this proposal are: Aim 1). To determine if stretch induced activation of MAPK family members is attenuated in aged muscle compared to adult muscle. Aim 2). To determine if the activity of FAK is increased by muscle stretch in adult and aged skeletal muscle. This work has broad application to basic and applied areas of the biomedical and health science fields. At the basic science level, these studies will increase our understanding of the pathways contractile tissues may use during the adaptation to altered loading conditions. At the more applied level, this research will provide will provide insight into the pathways regulating skeletal muscle hypertrophy, and to identify those pathways which could be targets for novel therapeutic strategies to prevent muscle wasting in patients and the frail elderly.