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

基本信息

项目摘要

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.
这项研究的目的是确定一种新的预防肌肉减少症干预措施。肌肉减少症 骨骼肌质量的普遍下降和逐渐下降,年龄伴随着任何降低 肌肉力量或身体表现。重要的是,骨骼肌质量和功能的丧失增加了 流动性,跌倒,骨折和死亡率受损的风险,是生活质量损害的主要因素 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,转移了收缩和非 - 收缩组织由于纤维萎缩,肌肉内肥胖和纤维化增加而导致。 目前,运动是显示肌肉减少症和药理学方法的唯一干预措施 完全缺乏。脂联素是脂肪组织衍生的肽多聚体,撞击骨骼肌 代谢激活脂质利用率和细胞呼吸道途径。我们的初步数据表明 脂联素受体激动剂adiporon激活与运动和有益作用有关的基因靶标 增强老年小鼠骨骼肌的收缩力。我们假设Adiporon将激活 骨骼肌线粒体和脂质燃料利用率,导致纤维收缩延迟,减少 与年龄相关的肌内肥胖和废除纤维化,并预防这些年龄 肌肉组成的相关变化将直接影响身体表现。 为了测试这一点,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肌肉减少症的一种手段。实验涉及 在肌肉减少症开发的早期和晚期,adiporon治疗 肌肉组成,身体表现和离体肌肉收缩力以及代谢评估 胃癌和比目鱼肌群。在AIM2机械研究中,我们将确定 代谢参数和细胞机制与骨骼肌肉衰老有关的脂肪龙。实验 专注于能量和氧化还原代谢,脂质代谢和炎症,包括有关该的新研究 线粒体乙酰基团和肌肉居民调节microRNA。拟议的研究已通知 通过我们先前在人类和非人类灵长类动物中的工作,很可能是高度翻译的。这些研究 具有创新性,因为他们在练习中引入了一种新颖的治疗性,并包括 机械和翻译成分。鉴定肌肉减少症的新型治疗干预措施 当今医疗保健的主要重点是 除衰老外,肌肉质量和功能的损失还可能是由于残疾或伤害而引起的。

项目成果

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Rozalyn M. Anderson其他文献

Adiponectin receptor agonist AdipoRon improves skeletal muscle function in aged mice
脂联素受体激动剂 AdipoRon 改善老年小鼠骨骼肌功能
  • DOI:
    10.1101/2021.09.16.460597
  • 发表时间:
    2021
  • 期刊:
  • 影响因子:
    7.7
  • 作者:
    Priya Balasubramanian;Anne E. Schaar;Grace E. Gustafson;Alex B Smith;Porsha R. Howell;A. Greenman;S. Baum;R. Colman;Dudley Lamming;G. Diffee;Rozalyn M. Anderson
  • 通讯作者:
    Rozalyn M. Anderson
Erratum to: COVID-19 Through the Lens of Gerontology
勘误表:老年学视角下的 COVID-19
Sex and Aging.
性与衰老。
Exploring Mechanisms of Aging Retardation by Caloric Restriction: Studies in Model Organisms and Mammals
探索热量限制延缓衰老的机制:对模式生物和哺乳动物的研究
  • DOI:
    10.1007/978-90-481-3465-6_4
  • 发表时间:
    2010
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Rozalyn M. Anderson;R. Colman;R. Weindruch
  • 通讯作者:
    R. Weindruch
The caloric restriction paradigm
热量限制范式
  • DOI:
  • 发表时间:
    2015
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Rozalyn M. Anderson
  • 通讯作者:
    Rozalyn M. Anderson

Rozalyn M. Anderson的其他文献

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{{ truncateString('Rozalyn M. Anderson', 18)}}的其他基金

Molecular Networks in Aging and Caloric Restriction in Rhesus Monkeys
恒河猴衰老和热量限制的分子网络
  • 批准号:
    10579229
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
Biological Sciences Program at The Gerontological Society of America's 2022 Annual Scientific Meeting
美国老年学会 2022 年科学年会生物科学项目
  • 批准号:
    10469163
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
Molecular Networks in Aging and Caloric Restriction in Rhesus Monkeys
恒河猴衰老和热量限制的分子网络
  • 批准号:
    10392035
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
Metabolism of Alzheimer’s Disease: systems and cellular networks
阿尔茨海默病的代谢:系统和细胞网络
  • 批准号:
    10189472
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Metabolism of Alzheimer’s Disease: systems and cellular networks
阿尔茨海默病的代谢:系统和细胞网络
  • 批准号:
    10634691
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
Metabolism of Alzheimer’s Disease: systems and cellular networks
阿尔茨海默病的代谢:系统和细胞网络
  • 批准号:
    10407033
  • 财政年份:
    2020
  • 资助金额:
    --
  • 项目类别:
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
  • 财政年份:
    2018
  • 资助金额:
    --
  • 项目类别:
Reproductive Hormones in Skeletal Muscle Aging in Rhesus Monkeys
恒河猴骨骼肌老化中的生殖激素
  • 批准号:
    9118623
  • 财政年份:
    2015
  • 资助金额:
    --
  • 项目类别:
Caloric Restriction and Aging in Rhesus Monkeys
恒河猴的热量限制和衰老
  • 批准号:
    9884520
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:
Caloric Restriction and Aging in Rhesus Monkeys
恒河猴的热量限制和衰老
  • 批准号:
    9101195
  • 财政年份:
    2011
  • 资助金额:
    --
  • 项目类别:

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肥胖和非肥胖成人被动和主动全身热应激反应的特征
  • 批准号:
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