Impact of Alcohol on Aging Skeletal Muscle

酒精对衰老骨骼肌的影响

• 批准号: 10510586
• 负责人: Jennifer Lynn Steiner
• 金额: $ 7.7万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10510586
• 关键词: Address; Adult; Affect; Age-Months; Aging; Alcohol consumption; Alcohols; Area; Attenuated; Chronic; Collagen; Consumption; Cross-Sectional Studies; Data; Deposition; Development; Disease; Dose; Elderly; Ethics; Etiology; Fatigue; Fatty acid glycerol esters; Female; Fiber; Foundations; Future; Goals; Guidelines; Hand Strength; Health; Health Benefit; Human; Impairment; In Situ; Incidence; Infiltration; Intake; Investigation; Knowledge; Leg; Longevity; Maintenance; Measurement; Mitochondria; Mus; Muscle; Muscle Mitochondria; Muscular Atrophy; Myopathy; Outcome; Performance; Pharmacology; Physical Function; Physical Performance; Population; Pre-Clinical Model; Prevention; Process; Production; Property; Prospective cohort study; Public Health; Quality of life; Randomized Controlled Trials; Recommendation; Research; Risk; Rodent; Role; Skeletal Muscle; Testing; Tissues; Type 2 diabetic; Water; Weight; Woman; Work; aged; alcohol effect; alcohol measurement; alcoholic myopathy; dietary; disability; falls; follow up assessment; frailty; human old age (65+); improved; interest; lifestyle factors; male; men; metabolic rate; middle age; mortality; mouse model; muscle aging; muscle form; muscle metabolism; muscle strength; performance tests; pre-clinical; prevent; problem drinker; reduced muscle strength; response; sarcopenia; sex; skeletal muscle wasting; unethical

Project Summary/Abstract Aging-related sarcopenia includes the loss of muscle mass and strength/function, which impairs mobility, increases falls, decreases independence and quality of life, and increases mortality. Alcohol use is among the lifestyle factors that may influence the development and progression of aging-related sarcopenia, as it promotes skeletal muscle myopathy in adults at high doses, and at low doses may improve mitochondrial function. Cross-sectional and prospective cohort studies indicate that high doses of alcohol are associated with greater incidence of sarcopenia while low to moderate intake is associated with maintenance of physical function and grip strength, as well as decreased frailty. As this dose dependent relationship has never been investigated experimentally in a well-controlled setting, the objective of this proposal is to develop and characterize a pre-clinical mouse model of aging to determine the dose- and sex-dependent effects of alcohol on aging-related sarcopenia. Relatedly, our long-term goal is to then investigate the potential paradoxical properties of alcohol on aging muscle while focusing on mechanisms that can be targeted pharmacologically to either limit or mimic the effects of each dose of alcohol. Specific Aim 1 will determine the dose-dependent effects of alcohol on the development and progression of aging related losses in skeletal muscle strength and performance, while Specific Aim 2 will investigate the effects of alcohol on aging related changes in skeletal muscle size and composition. These research questions will be addressed using middle aged (12 mo. old) male and female mice consuming either a high (15%v/v) or low (3.5%v/v) dose of alcohol in their water daily until reaching old age (~30 mo. old). Every 3 months performance tests and measurements of frailty, metabolic rate and cage activity will be completed. At 12 (baseline), 18, 24 and ~30 months of age, in-situ and ex vivo skeletal muscle force production and fatigability will be quantified on muscles of the lower leg. Follow-up assessments will include measurement of myofiber cross sectional area per fiber type and deposition of collagen and fat in the muscle. This will be the first investigation of the dose-dependent effects of alcohol on sarcopenia and will lay the foundation for future mechanistic investigations to determine how alcohol influences sarcopenia risk and aging associated changes to skeletal muscle in a sex-specific manner.

项目概要/摘要 与衰老相关的肌肉减少症包括肌肉质量和力量/功能的丧失，这会损害 行动不便，增加跌倒，降低独立性和生活质量，并增加死亡率。酒精的使用是 在可能影响与衰老相关的肌肉减少症发生和进展的生活方式因素中， 因为高剂量时它会促进成人骨骼肌肌病，而低剂量时可能会改善线粒体 功能。横断面和前瞻性队列研究表明，高剂量的酒精与 肌肉减少症的发生率较高，而低至中等摄入量与维持身体健康有关 功能和握力，以及降低脆弱性。由于这种剂量依赖性关系从未存在过 在良好控制的环境中进行实验研究，该提案的目标是开发和 表征临床前小鼠衰老模型，以确定酒精的剂量和性别依赖性影响 关于与衰老相关的肌肉减少症。相关地，我们的长期目标是调查潜在的矛盾 酒精对老化肌肉的作用，同时关注可针对其药理学作用的机制 限制或模仿每剂量酒精的影响。具体目标 1 将确定剂量依赖性 酒精对骨骼肌力量和衰老相关损失的发生和进展的影响 表现，而具体目标 2 将研究酒精对骨骼衰老相关变化的影响 肌肉的大小和组成。这些研究问题将通过中年人（12 个月大）来解决 雄性和雌性小鼠每天在水中饮用高剂量 (15%v/v) 或低剂量 (3.5%v/v) 酒精 直到老年（约30个月大）。每 3 个月进行一次性能测试以及虚弱、代谢测量 率和笼子活动将完成。 12（基线）、18、24 和 ~30 个月龄时，原位和离体 骨骼肌力量的产生和疲劳度将在小腿肌肉上进行量化。跟进 评估将包括测量每种纤维类型的肌纤维横截面积和沉积 肌肉中的胶原蛋白和脂肪。这将是首次研究酒精对人体的剂量依赖性影响 肌肉减少症，并将为未来的机制研究奠定基础，以确定酒精如何影响 肌肉减少症风险和衰老相关的骨骼肌变化具有性别特异性。