Adiponectin signaling in sarcopenia development and treatment

脂联素信号在肌肉减少症的发生和治疗中的作用

• 批准号: 10200659
• 负责人: Rozalyn M. Anderson
• 金额: --
• 依托单位: WM S. MIDDLETON MEMORIAL VETERANS HOSP
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200659
• 关键词: Adipose tissue; Adult; Age; Age-Years; Aging; Agonist; Animals; Area; Atrophic; Autopsy; Biological Assay; Body Composition; Cell Aging; Ceramides; Data; Development; Elderly; Energy Metabolism; Equilibrium; Event; Exercise; Fatty Acids; Fiber; Fibrosis; Fracture; Future; Gastrocnemius Muscle; Gene Targeting; Genetic Transcription; Goals; Hand Strength; Healthcare; Human; Impairment; In Situ; Inflammation; Inflammatory; Injury; Intervention; Intramuscular; Link; Lipids; Measures; Metabolic; Metabolic Pathway; Metabolism; MicroRNAs; Mitochondria; Molecular; Mus; Muscle; Muscle Mitochondria; Muscle function; Muscular Atrophy; National Health and Nutrition Examination Survey; Obesity; Outcome; Output; Oxidation-Reduction; Pathway interactions; Peptides; Pharmacology; Physical Performance; Population; Prevalence; Prevention; Process; Production; Proteins; Quality of life; Receptor Activation; Research; Risk; Rod; Running; Second Messenger Systems; Signal Transduction; Skeletal Muscle; Soleus Muscle; Testing; Therapeutic; Therapeutic Intervention; Tissues; Work; adiponectin; age related; aged; aging population; clinical application; clinically relevant; cytokine; disability; exhaustion; experimental study; falls; functional status; improved; indexing; innovation; insight; lipid metabolism; middle age; military veteran; mimetics; mortality; muscle aging; muscle form; nonhuman primate; novel; novel therapeutic intervention; novel therapeutics; prevent; receptor; reduced muscle strength; respiratory; sarcopenia; sensor; skeletal muscle metabolism; skeletal muscle wasting; translational study

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.

本研究的目的是确定预防和治疗肌肉减少症的新干预措施。少肌症是 随着年龄的增长，骨骼肌质量普遍逐渐下降，伴随着 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，是生活质量下降的一个主要因素 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 新陈代谢和成分预示着肌肉减少症的发生，改变了收缩性和非收缩性的平衡 由于纤维萎缩、肌内脂肪增加和纤维化增加而导致收缩组织。 目前，运动是治疗肌肉减少症的唯一干预措施，并且药物方法是 完全缺乏。脂联素是一种脂肪组织衍生的肽多聚体，会影响骨骼肌 代谢以激活脂质利用和细胞呼吸途径。我们的初步数据表明 脂联素受体激动剂 AdipoRon 激活与运动和运动有益效果相关的基因靶点 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利用，导致纤维收缩延迟，减少 与年龄相关的肌内肥胖和消除纤维化，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。 为了测试这一点，我们将进行以下研究： 在 Aim1 转化研究中，我们将确定 脂联素受体激活作为预防和治疗小鼠肌肉减少症的一种手段。实验涉及 AdipoRon 在肌肉减少症发展的早期和晚期进行治疗，包括评估 肌肉成分、身体表现和离体肌肉收缩力以及代谢评估 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 重点关注能量和氧化还原代谢、脂质代谢和炎症，并包括关于 线粒体乙酰组和肌肉驻留调节 microRNA。拟议的研究已被告知 根据我们之前在人类和非人类灵长类动物身上所做的工作，并且可能具有高度可翻译性。这些研究 具有创新性，因为他们在模拟运动 AdipoRon 中引入了一种新颖的治疗方法，包括 机械和翻译组件。肌肉减少症的新型治疗干预措施的确定 是当今医疗保健的一个重点，并且在临床上与退伍军人群体相关，其中 除了衰老之外，残疾或受伤也可能导致肌肉质量和功能的丧失。