The role of ghrelin and the ghrelin receptor GHSR1a in sarcopenia of aging

描述（申请人提供）：肌少症是一种与肌肉质量和功能减少有关的疾病，常见于老年人，也是许多慢性疾病如癌症、阻塞性肺病和心力衰竭的严重并发症。这是一个值得关注的问题，因为肌肉减少症与功能不良、日常生活活动能力受损、独立性丧失和死亡率增加有关。尽管骨骼肌减少症给老年人带来了沉重的负担，但目前尚无有效的治疗方法。骨骼肌减少症的发生涉及多种机制，包括蛋白质合成减少、蛋白质水解增加和核因子引起的炎症。B (NF吗?B)端依赖途径。新出现的证据表明，生长素调节着这些和其他影响肌肉质量的途径。然而，胃饥饿素对肌肉质量和功能的影响及其在衰老肌肉减少症中的作用机制尚不清楚。本应用的长期目标是建立ghrelin及其受体GHSR1a在衰老肌肉减少症中的作用机制。我们假设胃饥饿素通过：a)增加蛋白质合成和减少蛋白质水解，b)下调炎症和NF？B激活，c)这些作用至少部分是通过ghrelin受体GHSR1a介导的。我们的具体目的是确定在这种情况下ghrelin和GHSR1a在调节肌肉质量和功能中的作用。利用我们的衰老相关肌肉减少症模型，我们将：1)确定胃饥饿素在多大程度上调节肌肉质量、肌肉性能、蛋白质合成和蛋白质水解；2)表征胃饥饿素在调节炎症和NF中的作用？3)确定ghrelin受体GHSR1a在这种情况下的作用。设计和方法：我们将通过在ghrelin和GHSR-1a野生型和KO动物的背景下建立我们最近开发的衰老肌肉减少模型来表征ghrelin和GHSR-1a的作用。此外，我们将建立炎症和NF？利用转基因小鼠系，在含有NF?的启动子控制下表达荧光素酶和绿色荧光蛋白。B共识结合位点。体外研究也将进行，以进一步表征调解胃饥饿素的作用机制。意义：本研究将确立ghrelin和GHSR1a在老年性肌肉减少症中的作用，为其治疗开辟新的途径。功能表现的改善将允许个人在家里呆得更久，减少住院治疗，提高生活质量，降低医疗费用。改善这些结果可能会延长寿命。

DESCRIPTION (provided by applicant): Sarcopenia, the association of decreased muscle mass and function, is commonly seen in the elderly and it is also a serious complication of many chronic diseases such as cancer, obstructive lung disease and heart failure. This is of significant concern because sarcopenia is associated with poor functionality, impaired ability to perform activities of daily living, loss of independence and increased mortality. There are currently no available treatments for this condition despite the significant burden that sarcopenia represents to the elderly. Several mechanisms are involved in the development of sarcopenia including decreased protein synthesis, increased proteolysis and inflammation through nuclear factor ?B (NF?B)-dependent pathways. Emerging evidence suggests that the hormone ghrelin regulates these and other pathways affecting muscle mass. However, ghrelin's effects on muscle mass and function and the mechanisms mediating its effects in the setting of sarcopenia of aging are not known. The long-term objectives of this application are to establish the mechanisms mediating the action of ghrelin and the ghrelin receptor GHSR1a in sarcopenia of aging. We hypothesize that ghrelin prevents aging-associated sarcopenia by: a) Increasing protein synthesis and decreasing proteolysis, b) downregulating inflammation and NF?B activation, and c) that these effects are at least partially mediated through the ghrelin receptor GHSR1a. Our specific aims are to determine the role of ghrelin and the GHSR1a in regulating muscle mass and function in this setting. Using our model of aging-associated sarcopenia, we will: 1) Establish the extent to which muscle mass, muscle performance, protein synthesis and proteolysis are regulated by ghrelin, 2) Characterize the role of ghrelin in modulating inflammation and NF?B activation during aging, and 3) Determine the role of the ghrelin receptor GHSR1a in this setting. Design and methods: We will characterize the role of ghrelin and the GHSR-1a by establishing our recently developed model of sarcopenia of aging in the background of ghrelin and GHSR-1a wild type and KO animals. Furthermore, we will establish the role of inflammation and NF?B activity by exploiting a transgenic mouse line that has been engineered to express luciferase and green fluorescent protein under control of a promoter that contains NF?B consensus binding sites. In-vitro studies will also be performed to further characterize the mechanisms mediating ghrelin's action. Significance: The present proposal will establish the role of ghrelin and the GHSR1a in the setting of sarcopenia of aging, opening new avenues for its treatment. An improvement in functional performance would allow individuals to stay home longer, decreasing hospitalizations, improving quality of life and reducing healthcare costs. It is possible that improving these outcomes will increase longevity. PUBLIC HEALTH RELEVANCE: The loss of muscle mass and function known as sarcopenia is very common in the elderly, reducing functionality and quality of life, and increasing mortality. The novel hormone ghrelin may prevent the development of sarcopenia and this proposal will determine its effects and mechanisms of action in this setting. The results generated by these studies will help us to develop treatments for sarcopenia; thereby improving quality of life by allowing patients to stay home longer, decreasing the need for hospitalizations and reducing the cost of healthcare.