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进行性下降有关，这对 能够保持独立的生活方式；导致老年人身体虚弱和行动不便 成年人。衰老还与对来自活动的增长线索作出反应的能力降低有关 例如，抗阻运动和在不活动或受伤后恢复负重。无能为力 或在长时间卧床休息或不活动后恢复肌肉大小 加速骨质疏松症的进展，并导致功能活动能力、独立性的丧失 和脆弱的开始。拟议的研究与退伍军人管理局特别相关 由于该系统内的相当数量的患者将作为一种 卧床休息、动弹不得或神经损伤的后果。此外，肌肉萎缩的影响更大 随着年龄的增长，身体虚弱，导致住院时间更长，活动能力和独立性下降， 跌倒，和长期残疾。由于老年退伍军人的人数正在上升，这个问题代表着一个 退伍军人管理局日益受到医疗和金钱方面的关注。因此，这项研究的长期目标 这项建议是为了通过开发有效的治疗方法来解决一个重要的未得到满足的临床需求。 用于促进肌肉萎缩后的恢复。根据我们最近的发现，我们假设 老年动物因废用而导致的萎缩后缺乏功能恢复的部分原因与 停用过程中神经肌肉接头损伤增加，重新加载后会恶化。最新研究 提示饮食中补充长链omega-3脂肪酸对肌肉质量和 然而，力量输出还需要进一步的研究。这项建议的目的是测试饮食的能力 补充鱼油，防止肌肉质量和功能随着年龄的增长而丧失，并增强 废用性萎缩后肌肉质量和功能的恢复。这些研究将使用一种动物 对人类有出色翻译应用的模型：费舍尔·布朗挪威F1杂交大鼠 (FBNF1)。完成这项提案中概述的具体目标将提供数据，说明鱼油是否是一种 潜在的治疗骨质疏松症和/或可以促进肌肉质量和功能的恢复 废止萎缩。这些研究还将提供有关石棺减少的机制和 与年龄相关的生长能力丧失。在特定目标1中，我们将测试补充鱼油的能力 促进老年雄性FBNF1大鼠后肢负重所致肌肉萎缩的恢复。年长的 大鼠将在后肢卸载前接受8周负荷量的鱼油补充， 这将持续整个14天的卸货和14天的重新装货。在具体目标2中，我们将 确定9个月的饮食补充鱼油是否可以预防或减轻肌肉质量的损失 雄鼠和雌鼠的体力。饮食补充将在22个月龄的雄性和 女性20个月龄；后肢肌肉质量和功能未显著丧失的年龄 可测量的。雄性大鼠(20至29个月)将在22至31个月的多个时间点对其实施安乐死 女性)，以监测肌肉质量和力量的丧失，并检查潜在的分子和 骨质疏松症的细胞机制和鱼油治疗的潜在作用机制。