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.

总结 老年虚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， 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。虚弱 经常导致功能独立性的丧失，并且是老年人福尔斯跌倒的主要危险因素之一。在 事实上，随着预期寿命的不断增加，肌肉力量的维持是一个重要因素， 有助于提高生活质量。虽然肌肉减少症的病因仍有待确定，建议 影响因素包括神经支配和运动单位衰退的丧失、氧化应激、异常自噬 和炎症。有新的证据表明存在肠骨骼肌轴。的基础上 这种联系，有很多猜测，肠道微生物群的生态失调可能在肠道疾病中发挥作用。 肌肉减少症的发展。虽然已经提出了合理的机制，通过这些机制，生态失调可能 有助于肌肉减少症的发展，仍然缺乏直接证据支持这种 机制等这项探索性资助的目的是检验肠道微生物群的生态失调 通过TLR 4诱导骨骼肌中的合成代谢抵抗状态促进肌肉减少症 mTORC 1信号传导的过度激活。为了检验这一假设，将追求以下目标：目标1： 确定来自老年小鼠的肠道微生物群是否可以诱导成年小鼠的肌肉减少症;目的2：确定来自老年小鼠的肠道微生物群是否可以诱导成年小鼠的肌肉减少症。 来自成年小鼠的肠道微生物群可以挽救老年小鼠的肌肉减少症。如果实验的结果 提供证据来支持假设，未来的R 01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TLR 4敲除是否可以预防肌肉减少症， 由肠道微生物群生态失调引起的全身性炎症。