Adiponectin signaling in sarcopenia development and treatment

这项研究的目的是确定一种预防和治疗石棺减少症的新干预措施。骨质疏松症 随着年龄的增长，骨骼肌质量的普遍和进行性下降，伴随着其中之一的减少 肌肉力量或身体表现。重要的是，骨骼肌质量和功能的丧失会增加 活动能力受损、跌倒、骨折和死亡的风险，是影响生活质量和 失去独立性。我们对非人类灵长类动物的研究表明，骨骼肌的变化 新陈代谢和成分预示着骨质疏松症的发生，改变了收缩和非收缩的平衡. 由于纤维萎缩、肌肉内脂肪增多和纤维化加重而导致的收缩组织。 目前，运动是治疗石棺减少症的唯一干预措施，而药理学方法是 完全缺乏。脂联素是一种作用于骨骼肌的脂肪组织衍生肽多聚体 新陈代谢，激活脂质利用和细胞呼吸途径。我们的初步数据显示 脂联素受体激动剂AdipoRon激活参与运动和运动有益效果的基因靶点 增强衰老小鼠骨骼肌收缩力。我们假设AdipoRon将激活 骨骼肌线粒体和脂肪燃料的利用，导致延迟性纤维收缩，减少 与年龄相关肌肉内肥胖症和被消除的纤维化，以及预防这些年龄- 肌肉成分的相关变化将直接影响身体表现。 为了验证这一点，我们将进行以下研究：在Aim1翻译研究中，我们将确定 脂联素受体激活作为预防和治疗小鼠骨质疏松症的手段。实验涉及到 AdipoRon在骨质疏松症早期和晚期的治疗，并包括对 研究对象的肌肉成分、体能表现和体外肌肉收缩能力以及代谢评估 腓肠肌和比目鱼肌群。在AIM2机制研究中，我们将确定 AdipoRon对与骨骼肌衰老有关的代谢参数和细胞机制的研究。实验 重点关注能量和氧化还原代谢、脂肪代谢和炎症，并包括关于 线粒体乙酰体和肌肉驻留调节microRNA。建议的研究已被告知 通过我们之前在人类和非人类灵长类动物上的研究，很可能是高度可翻译的。这些研究 是创新的，因为他们在运动中引入了一种新的治疗模拟AdipoRon，包括 机械部件和平移部件。石棺减少症新的治疗措施的确定 构成了当今卫生保健的一个主要重点，在临床上与退伍军人群体有关， 除了衰老之外，肌肉质量和功能的丧失也可能是由于残疾或损伤引起的。

The goal of this study is to identify a novel intervention for sarcopenia prevention and treatment. Sarcopenia is the generalized and progressive decline in skeletal muscle mass with age accompanied by either reduced muscle strength or physical performance. Importantly, loss of skeletal muscle mass and function increases the risk for impaired mobility, falls, fractures and mortality and is a major factor in compromised quality of life and loss of independence. Our studies in nonhuman primates have shown that changes in skeletal muscle metabolism and composition anticipate the onset of sarcopenia, shifting the balance of contractile and non- contractile tissue as a result of fiber atrophy, increased intramuscular adiposity, and increased fibrosis. Currently, exercise is the only intervention shown to treat sarcopenia and pharmacological approaches are entirely lacking. Adiponectin is an adipose tissue-derived peptide multimer that impinges on skeletal muscle metabolism to activate lipid utilization and cellular respiratory pathways. Our preliminary data show that the adiponectin receptor agonist AdipoRon activates gene targets involved in the beneficial effects of exercise and enhances contractile force in skeletal muscle from aged mice. We hypothesize that AdipoRon will activate skeletal muscle mitochondria and lipid fuel utilization, resulting in delayed fiber shrinkage, reduced age-associated intramuscular adiposity, and abrogated fibrosis, and that prevention of these age- related changes in muscle composition will directly impinge on physical performance. To test this we will conduct the following studies: In Aim1 translational studies, we will determine the efficacy of adiponectin receptor activation as a means to prevent and treat sarcopenia in mice. Experiments involve AdipoRon treatment in the early and late stages of sarcopenia development and include assessments of muscle composition, physical performance and ex vivo muscle contractile force, and metabolic assessments in gastrocnemius and soleus muscle groups. In Aim2 mechanistic studies, we will determine the impact of AdipoRon on metabolic parameters and cellular mechanisms implicated in skeletal muscle aging. Experiments focus on energy and redox metabolism, lipid metabolism, and inflammation and include novel studies on the mitochondrial acetylome and muscle resident regulatory microRNA. The proposed studies have been informed by our prior work in humans and nonhuman primates and are likely to be highly translatable. These studies are innovative as they introduce a novel therapeutic in the exercise mimetic AdipoRon and include mechanistic and translational components. The identification of novel therapeutic interventions for sarcopenia constitutes a major emphasis in health care today and is clinically relevant to veterans populations where loss of muscle mass and function can arise from disability or injury in addition to aging.