Impact of Alcohol on Aging Skeletal Muscle

项目总结/摘要 衰老相关的肌肉减少症包括肌肉质量和力量/功能的损失，这损害了 活动性，增加福尔斯，降低独立性和生活质量，并增加死亡率。饮酒是 在可能影响与衰老相关的肌肉减少症的发展和进展的生活方式因素中， 因为它在高剂量时促进成人骨骼肌肌病，而在低剂量时可能改善线粒体 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更高，而低至中等摄入量与维持身体健康有关。 功能和握力，以及减少虚弱。由于这种剂量依赖关系从未被 在控制良好的环境中进行实验研究，本提案的目的是开发和 表征衰老的临床前小鼠模型，以确定酒精的剂量和性别依赖性效应 关于衰老相关的肌肉减少症与此相关，我们的长期目标是研究潜在的悖论， 酒精对衰老肌肉的特性，同时专注于可以有针对性地 限制或模拟每剂酒精的作用。具体目标1将确定剂量依赖性 酒精对骨骼肌强度和骨骼肌强度的老化相关损失的发展和进展的影响 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。这些研究问题将使用中年（12个月）。旧） 雄性和雌性小鼠每天在水中摄入高剂量（15%v/v）或低剂量（3.5%v/v）的酒精 直到达到老年（约30个月）。旧的）。每3个月进行一次体能测试和虚弱、代谢测量 将完成速率和笼活动。在12（基线）、18、24和~30月龄时，原位和离体 将对小腿肌肉的骨骼肌力产生和疲劳性进行量化。后续行动 评估将包括测量每种纤维类型的肌纤维横截面积和 肌肉中的胶原蛋白和脂肪这将是第一次研究酒精的剂量依赖性影响， 并将为未来的机制研究奠定基础，以确定酒精如何影响 肌肉减少症的风险和骨骼肌以性别特异性方式的衰老相关变化。

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.