Sarcopenia and recovery from Disuse-Induced Atrophy

衰老过程与运动功能的进行性下降有关，这对运动功能有重大影响。 维持独立生活方式的能力;导致老年人中观察到的虚弱和丧失活动能力 成年人了衰老还与对来自活动的生长线索的反应能力降低有关 例如抵抗运动和在不活动或受伤后恢复负重。无法回应 机械负荷或恢复长时间卧床休息或不活动后的肌肉大小 加速肌肉减少症的进展，并导致功能性活动、独立性 和脆弱的开始拟议中的研究与退伍军人管理局特别相关 由于系统内相当多的患者将遭受骨骼肌萎缩， 卧床休息、固定或神经创伤的后果。此外，肌肉萎缩的影响更多 随着年龄的增长而衰弱，导致住院时间延长，活动性和独立性下降， 福尔斯和长期残疾。由于老年退伍军人的人口正在增加，这个问题代表了一个 对退伍军人事务部的医疗和经济问题的担忧因此，研究的长期目标概述于 该提案旨在通过开发有效的治疗方法来解决一个重要的未满足的临床需求 用于增强萎缩后的肌肉恢复。基于我们最近的发现，我们假设 老年动物废用性萎缩后缺乏功能恢复，部分与 在重新负荷时，在废用肌群期间神经肌肉接头损伤增加。最近的研究 表明饮食中补充长链欧米茄-3脂肪酸对肌肉质量有益， 然而，需要进一步研究。本提案的目的是测试饮食的能力， 补充鱼油，以防止肌肉质量和功能随年龄增长而丧失， 废用性萎缩后肌肉质量和功能的恢复。这些研究将使用动物 对人类具有突出转化应用的模型：Fischer Brown Norway F1杂交大鼠 （FBNF 1）。完成本提案中概述的具体目标将提供有关鱼油是否是一种 用于肌肉减少症的潜在治疗和/或可以增强肌肉质量和功能的恢复， 废用性萎缩这些研究还将提供有关肌肉减少症机制的信息， 与年龄相关的生长能力丧失。在具体目标1中，我们将测试鱼油补充剂的能力， 促进老年雄性FBNF 1大鼠后肢去负荷引起的肌肉萎缩的恢复。老 大鼠将在后肢卸载之前接受8周负荷剂量的膳食鱼油补充剂， 这将持续14天的卸载和14天的重新装载。在具体目标2中， 确定9个月的膳食鱼油补充剂是否可以预防或减轻肌肉质量的损失 和力量。在22个月大的雄性中，将开始饮食补充， 雌性20月龄;后肢肌肉质量和功能不显著丧失的年龄 可测量的在22至31个月的多个时间点对雄性大鼠实施安乐死（20至29 在女性中为3个月），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治疗的潜在作用机制。

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.