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

描述（由申请人提供）：肌肉减少症，即肌肉质量和功能下降的相关性，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。这是一个重要的问题，因为肌肉减少症与功能差、进行日常生活活动的能力受损、丧失独立性和死亡率增加有关。尽管肌肉减少症给老年人带来了巨大的负担，但目前还没有针对这种病症的可用治疗方法。肌肉减少症的发生与多种机制有关，包括蛋白质合成减少、蛋白质水解增加和核因子介导的炎症反应。B（NF？B）依赖性途径。新出现的证据表明，激素生长激素调节这些和其他影响肌肉质量的途径。然而，ghrelin对肌肉质量和功能的影响以及在衰老的肌肉减少症的背景下介导其作用的机制尚不清楚。 本申请的长期目标是建立介导生长素释放肽和生长素释放肽受体GHSR 1a在衰老性肌肉减少症中的作用的机制。我们推测ghrelin通过以下途径预防衰老相关的肌肉减少症：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，和c）这些作用至少部分通过生长素释放肽受体GHSR 1 a介导。我们的具体目标是确定ghrelin和GHSR 1a在这种情况下调节肌肉质量和功能的作用。使用我们的模型与年龄相关的肌肉减少症，我们将：1）建立在何种程度上肌肉质量，肌肉性能，蛋白质合成和蛋白质水解的调节ghrelin，2）表征ghrelin在调节炎症和NF？B在老化过程中的激活，以及3）确定生长激素释放肽受体GHSR 1a在这种情况下的作用。设计和方法：我们将通过在生长素释放肽和GHSR-1a野生型和KO动物的背景下建立我们最近开发的衰老性少肌症模型来表征生长素释放肽和GHSR-1a的作用。此外，我们将建立炎症和NF？B活性，通过利用转基因小鼠系，已被改造为表达荧光素酶和绿色荧光蛋白的启动子，包含NF？B共有结合位点。还将进行体外研究以进一步表征介导生长激素释放肽作用的机制。重要性：本提案将确定ghrelin和GHSR 1a在衰老性肌肉减少症中的作用，为其治疗开辟新途径。功能性能的改善将使个人能够更长时间地呆在家里，减少住院，提高生活质量并降低医疗费用。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.