The role of the gut microbiota in sarcopenia

肠道微生物群在肌肉减少症中的作用

• 批准号: 10193399
• 负责人: JOHN Joseph MCCARTHY
• 金额: $ 22.24万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10193399
• 关键词: Adult; Age; Age-Months; Aging; Amino Acids; Autophagocytosis; Biological Assay; Cell Count; Cell physiology; Defect; Development; Elderly; Endocrine; Etiology; Exercise; Exhibits; Fiber; Fibrosis; Future; Grant; Impairment; Inflammation; Injury; Interleukin-6; Intestinal permeability; Intestines; Investigation; Knock-out; Life Expectancy; Maintenance; Measures; Metabolic; Motor; Mus; Muscle; Muscle function; Oxidative Stress; Performance; Persons; Phenotype; Polyethylene Glycols; Population; Predisposition; Quality of life; Research; Resistance; Risk Factors; Role; Serum; Signal Transduction; Skeletal Muscle; TLR4 gene; TNF gene; Testing; Woman; aged; dysbiosis; experimental study; falls; fecal microbiota; fluorescein isothiocyanate dextran; frailty; functional independence; functional loss; gut bacteria; gut dysbiosis; gut microbiome; gut microbiota; improved; men; mitochondrial DNA mutation; muscle aging; muscle form; muscle strength; nerve supply; novel; prevent; regeneration following injury; response; sarcopenia; satellite cell; sedentary; skeletal muscle wasting; systemic inflammatory response; therapeutic target

Summary A key determinant of geriatric frailty is sarcopenia, the age-associated loss of skeletal muscle mass and function. Recent estimates indicate that up to one-third of the elderly population may suffer from frailty. Frailty often leads to loss of functional independence and is among the leading risk factors for falls in the elderly. In fact, as life expectancy continues to increase, the maintenance of muscle strength is an important factor that contributes to a higher quality of life. Although the etiology of sarcopenia remains to be determined, proposed contributing factors include the loss of innervation and motor unit decline, oxidative stress, aberrant autophagy and inflammation. There is emerging evidence for the existence of a gut-skeletal muscle axis. On the basis of this connection, there has been much speculation that dysbiosis of the gut microbiota might have a role in the development of sarcopenia. While plausible mechanisms have been proposed through which dysbiosis might contribute to the development of sarcopenia, there remains a paucity of direct evidence to support such mechanisms. The purpose of this exploratory grant is to test the hypothesis that dysbiosis of the gut microbiota promotes sarcopenia by inducing a state of anabolic resistance in skeletal muscle through TLR4 hyperactivation of mTORC1 signaling. To test this hypothesis, the following aims will be pursued: Aim 1: Determine if the gut microbiota from aged mice can induce sarcopenia in adult mice; Aim 2: Determine if the gut microbiota from adult mice can rescue sarcopenia in old mice. If the results of the proposed experiments provide evidence to support the hypothesis, a future R01 application will seek to rigorously test the proposed mechanism by determining if a skeletal muscle-specific TLR4 knockout prevents sarcopenia despite low-grade systemic inflammation induced by gut microbiota dysbiosis.

概括 老年衰弱的一个关键决定因素是肌肉减少症，即与年龄相关的骨骼肌质量损失和 功能。最近的估计表明，多达三分之一的老年人口可能患有虚弱症。虚弱 通常会导致功能独立性的丧失，并且是老年人跌倒的主要危险因素之一。在 事实上，随着寿命的不断延长，肌肉力量的维持是一个重要因素 有助于提高生活质量。尽管肌肉减少症的病因仍有待确定，但建议 影响因素包括神经支配丧失和运动单位衰退、氧化应激、异常自噬 和炎症。越来越多的证据表明肠道-骨骼肌轴的存在。基于 这种联系，有很多猜测认为肠道微生物群的失调可能在 肌肉减少症的发展。虽然已经提出了可能通过菌群失调的合理机制 有助于肌肉减少症的发展，但仍然缺乏直接证据支持这种情况 机制。这项探索性资助的目的是检验肠道微生物群失调的假设 通过 TLR4 诱导骨骼肌合成代谢抵抗状态，从而促进肌肉减少症 mTORC1 信号传导过度激活。为了检验这一假设，将追求以下目标： 目标 1： 确定老年小鼠的肠道微生物群是否会诱发成年小鼠肌肉减少症；目标 2：确定是否 成年小鼠的肠道微生物可以挽救老年小鼠的肌肉减少症。如果建议的实验结果 提供证据支持该假设，未来的 R01 应用程序将寻求严格测试所提出的 通过确定骨骼肌特异性 TLR4 敲除是否可以预防低级别肌肉减少症来研究机制 肠道微生物群失调引起的全身炎症。