Adiponectin signaling in sarcopenia development and treatment

本研究的目的是确定一种新的干预措施，用于预防和治疗肌肉减少症。肌肉减少症是 骨骼肌质量随着年龄的增长而普遍和进行性下降， 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、福尔斯、骨折和死亡的风险，是影响生活质量的主要因素， 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 代谢和组成预测肌肉减少症的发作，改变收缩和非收缩的平衡， 由于纤维萎缩、肌内肥胖增加和纤维化增加导致的收缩组织。 目前，运动是治疗肌肉减少症的唯一干预措施， 完全缺乏。脂联素是一种脂肪组织来源的多肽多聚体，作用于骨骼肌 代谢以激活脂质利用和细胞呼吸途径。初步数据显示， 脂联素受体激动剂AdipoRon激活参与运动有益作用的基因靶点， 增强老年小鼠骨骼肌的收缩力。我们假设AdipoRon会激活 骨骼肌线粒体和脂质燃料的利用，导致延迟纤维收缩，减少 与年龄相关肌内肥胖和纤维化消失，以及预防这些年龄- 肌肉组成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Aim 1翻译研究中，我们将确定 脂联素受体活化作为预防和治疗小鼠肌肉减少症的手段。实验涉及 AdipoRon治疗肌肉减少症发展的早期和晚期阶段，包括评估 肌肉组成、体能和离体肌肉收缩力，以及代谢评估， 腓肠肌和比目鱼肌群。在目标2机制研究中，我们将确定以下因素的影响： AdipoRon对骨骼肌衰老相关代谢参数和细胞机制的影响实验 侧重于能量和氧化还原代谢，脂质代谢和炎症，并包括新的研究 线粒体乙酰组和肌肉驻留调节microRNA。已通知拟议的研究 通过我们先前在人类和非人类灵长类动物中的工作，很可能是高度可翻译的。这些研究 是创新的，因为他们在运动模拟AdipoRon中引入了一种新的治疗方法， 机械和平移组件。肌肉减少症的新型治疗干预措施的确定 构成了当今医疗保健的一个主要重点，并与退伍军人群体临床相关， 肌肉质量和功能的丧失除了衰老之外还可由残疾或损伤引起。

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.