Sarcopenia and recovery from Disuse-Induced Atrophy

肌肉减少症和废用性萎缩的恢复

• 批准号: 10549727
• 负责人: Sue C Bodine
• 金额: --
• 依托单位: OKLAHOMA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549727
• 关键词: Acceleration; Acute; Address; Age; Age Months; Aging; Animal Model; Animals; Atrophic; Attenuated; Bed rest; Clinical; Cues; Data; Denervation; Development; Diet; Dietary Supplementation; Disuse Atrophy; Dose; Elderly; Euthanasia; Event; Female; Fish Oils; Gene Expression; Genetic Transcription; Goals; Growth; Hindlimb Suspension; Human; Hybrids; Immobilization; Impairment; Individual; Injury; Length of Stay; Life Style; Limb structure; Medical; Modeling; Molecular; Monitor; Motor; Muscle; Muscle Fibers; Muscle function; Muscular Atrophy; Nerve; Neuromuscular Junction; Norway; Older Population; Omega-3 Fatty Acids; Output; Pathway interactions; Patients; Persons; Pharmacologic Substance; Process; Rattus; Recovery; Recovery of Function; Rehabilitation therapy; Research; Rodent; Skeletal Muscle; Supplementation; System; Testing; Time; Trauma; Traumatic injury; United States Department of Veterans Affairs; Veterans; Weight-Bearing state; age-related muscle loss; aged; aging population; cohort; dietary; disability; effective therapy; effectiveness testing; falls; fatty acid supplementation; frailty; functional loss; impaired capacity; improved; insight; male; mechanical load; middle age; muscle form; muscle strength; neural; prevent; programs; resistance exercise; sarcopenia; skeletal muscle wasting; therapeutically effective; translational applications

The aging process is associated with a progressive decline in motor function that has a major impact on the ability to maintain an independent lifestyle; contributing to the frailty and loss of mobility observed in older adults. Aging is also associated with a reduced capacity to respond to growth cues derived from activities such as resistance exercise and return to weight bearing following inactivity or injury. An inability to respond to mechanical loading or to restore muscle size following extended periods of bed rest or inactivity accelerates the progression of sarcopenia and contributes to the loss of functional mobility, independence and the onset of frailty. The proposed research is of particular relevance to the Veteran’s Administration since a significant number of patients within the system will suffer skeletal muscle atrophy as a consequence of bed rest, immobilization, or neural trauma. Further, the effects of muscle atrophy are more debilitating with age resulting in longer hospital stays, a decrease in mobility and independence, an increase in falls, and long-term disability. Since the population of older veterans is rising, this issue represents a growing medical and monetary concern for the VA. Thus, the long-term objective of the research outlined in this proposal is to address an important unmet clinical need through the development of effective therapies for the enhancement of muscle recovery following atrophy. Based on our recent findings, we hypothesize that the lack of functional recovery following disuse-induced atrophy in aged animals is related, in part, to an increase in neuromuscular junction impairment during disuse that worsens upon reloading. Recent studies suggest that diet supplementation with long-chain omega-3 fatty acids has benefits to muscle mass and force output, however, further study is needed. It is the objective of this proposal to test the ability of dietary supplementation with fish oil to prevent the loss of muscle mass and function with age and enhance the recovery of muscle mass and function following disuse-induced atrophy. These studies will use an animal model that has outstanding translational application to humans: the Fischer Brown Norway F1 hybrid rat (FBNF1). Completion of the specific aims outlined in this proposal will provide data on whether fish oil is a potential treatment for sarcopenia and/or can enhance the recovery of muscle mass and function from disuse atrophy. The studies will also provide information on the mechanisms involved in sarcopenia and age-associated loss of growth capacity. In specific aim 1 we will test the ability of fish oil supplementation to enhance the recovery of muscle from atrophy induced by hindlimb unloading in old male FBNF1 rats. Old rats will receive an 8-week loading dose of dietary fish oil supplementation prior to hindlimb unloading, which will continue throughout the 14 days of unloading and 14 days of reloading. In specific aim 2 we will determine if 9 months of dietary fish oil supplementation can prevent or attenuate the loss of muscle mass and strength in male and female rats. Dietary supplementation will begin at 22 months of age in males and 20 months of age in females; ages at which significant loss of hind limb muscle mass and function are not measurable. Rats will be euthanized at multiple time points between 22 and 31 months in males (20 to 29 months in females) to monitor the loss of muscle mass and strength and to examine potential molecular and cellular mechanisms of sarcopenia and potential mechanisms of action of the fish oil treatment.

衰老过程与运动功能的逐步下降有关，对 保持独立生活方式的能力；在较老的 成年人。衰老还与响应活动得出的增长线索的能力降低有关 例如抵抗运动，并在不活跃或伤害后恢复体重轴承。无法做出回应 延长床休息或不活动后，要进行机械载荷或恢复肌肉大小 加速肌肉减少症的进展，并导致功能流动性丧失，独立性 和脆弱的发作。拟议的研究与退伍军人政府特别相关 由于该系统中的大量患者会遭受骨骼肌萎缩 床休息，固定或神经创伤的结果。此外，肌肉萎缩的影响更多 随着年龄的增长而使人衰弱，导致住院时间更长，流动性和独立性下降，增加 在瀑布和长期残疾。由于老年退伍军人的人口正在增加，因此这个问题代表 对VA的医疗和货币关注不断增加。这是概述的研究的长期目标 该建议是通过开发有效的疗法来满足重要的未满足临床需求 为了增强萎缩后的肌肉恢复。根据我们最近的发现，我们假设 在老年动物中废除诱发萎缩后缺乏功能恢复与 在重新加载后破坏性期间，神经肌肉连接障碍的增加。最近的研究 建议补充长链omega-3脂肪酸对肌肉质量和 但是，需要进一步研究。该提议的目的是测试饮食的能力 补充鱼油，以防止肌肉质量的损失和随着年龄的增长而发挥作用 废弃诱发萎缩后的肌肉质量和功能的恢复。这些研究将使用动物 对人类具有出色翻译应用的模型：Fischer Brown Norway F1 Hybrid Rat （FBNF1）。该提案中概述的具体目的的完成将提供有关鱼油是否为一种的数据 肌肉减少症的潜在治疗和/或可以增强肌肉质量的恢复和功能 废除萎缩。研究还将提供有关肌肉减少症和涉及机制的信息 与年龄相关的增长能力丧失。在特定目标1中，我们将测试补充鱼油的能力 增强了在老雄性FBNF1大鼠中卸载后的肌肉中恢复肌肉的恢复。老的 大鼠将在后肢卸载之前接受8周的饮食鱼油补充剂量， 在整个卸货和重新加载14天的14天中，这将持续。在特定目标2中，我们将 确定补充饮食的9个月是否可以防止或减轻肌肉质量的损失 男性和雌性大鼠的力量。饮食补充剂将从男性22个月开始开始 女性20个月大；后肢肌肉质量和功能的重大损失不是年龄的年龄 可衡量。大鼠将在男性22到31个月之间多个时间点安乐死（20至29岁） 女性的月份），以监测肌肉质量和力量的损失，并检查潜在的分子和 肌肉减少症的细胞机制和鱼油处理的作用机理。