Iron Accumulation in Aging Skeletal Muscle

描述(由申请人提供)：随着年龄的增长，肌肉质量和质量的下降，称为骨质疏松症，可以严重限制功能能力和独立性，并导致生活质量下降。尽管在解开骨骼肌衰老过程中发生的许多功能和表型变化方面已经取得了进展，但关于触发这些适应的机制仍然存在问题。我们的长期目标是了解导致骨质疏松症发展的因素，从而促进更有效的治疗干预措施，以防止或延缓与衰老相关的肌肉损失。我们的小组最近发现了老年骨骼肌中非血红素铁水平升高的情况，并提出铁积累在骨质疏松症进展中的基本作用。随着年龄的增长，骨骼肌铁状态的增加可能是导致氧化应激和肌肉功能障碍的一个重要因素。目前的实验将利用一个被广泛接受的啮齿动物模型来描绘骨骼肌铁状态和随年龄增长而发生的调节变化的时间进程，并评估铁螯合疗法在缓解与衰老相关的骨骼肌减少方面的疗效。目的1是评估衰老对铁在骨骼肌铁分布和累积过程的影响。这些实验将揭示在衰老过程中骨骼肌中总的、非血红素的和血红素铁的分布。目的#2描述骨骼肌铁调节中与衰老相关的变化。阐明铁调节机制的时间响应将为了解导致铁积累的潜在因素提供必要的洞察力。目的#3是确定与衰老相关的铁积累对骨骼肌氧化损伤、萎缩和收缩功能障碍发展的影响。我们将利用长期服用铁络合剂吡哆醛异烟酰肼(PIH)来确定铁积累作为参与石棉减少症发展的一个因素的相对重要性。这些实验的结果将为铁在石棺减少的发展中的假定作用提供有价值的洞察，这将为未来RO1的应用提供必要的信息，目的是改善老年人的肌肉质量和功能。与公共健康相关：随着年龄的增长，肌肉质量和功能下降，称为石棺减少，这是一个与健康相关的重大问题，可能会限制一个人的功能独立性，并增加严重伤害的风险。肌肉中铁的积累可能是骨质疏松症发生的一个重要因素。这项工作与公众健康相关，其目的是揭示肌肉铁变化与石棺减少之间的关系，以便未来的研究能够以改善老年人的肌肉质量和功能为目标。

DESCRIPTION (provided by applicant): The decline in muscle mass and quality that occurs with advancing age, termed sarcopenia, can profoundly limit functional abilities, independence, and result in a decreased quality of life. Despite progress that has been made to unravel many of the functional and phenotypic changes that occur in skeletal muscle over the course of the aging process, questions remain regarding the mechanisms that trigger these adaptations. Our long- term goal is to understand factors which lead to the development of sarcopenia that may foster more effective therapeutic interventions to prevent or delay aging-related muscle loss. Our group has recently identified the occurrence of elevated non-heme iron levels in aged skeletal muscle and has suggested a fundamental role of iron accumulation in the progression of sarcopenia. The aging-associated increase in skeletal muscle iron status could be a vital factor leading to the development of oxidative stress and muscle dysfunction. The current experiments will utilize a well-accepted rodent model to delineate the time course of skeletal muscle iron status and regulation changes that occur with aging and to assess the efficacy of iron chelation therapy in the attenuation of aging-associated sarcopenia. Aim #1 is to evaluate the impact of aging on the iron distribution and progression of iron accumulation in skeletal muscle. These experiments will reveal total, non- heme, and heme iron distributions in skeletal muscle over the course of the aging process. Aim #2 is to delineate aging-related alterations in skeletal muscle iron regulation. Elucidation of the temporal response of iron regulation mechanisms will provide necessary insight into the potential factors that lead to iron accumulation. Aim #3 is to ascertain the impact of aging-associated iron accumulation on the development of skeletal muscle oxidative injury, atrophy, and contractile dysfunction. We will utilize prolonged administration of the iron chelator, pyridoxal isonicotinoyl hydrazone (PIH), to determine the relative importance of iron accumulation as a factor involved in the development of sarcopenia. The results of these experiments will provide valuable insight into the putative role of iron in the development of sarcopenia that will provide the necessary information for future RO1 applications with the objective of improving muscle quality and function of elderly individuals. PUBLIC HEALTH RELEVANCE: The decline in muscle quality and function with advancing age, termed sarcopenia, is a significant health- related concern that can limit a person's functional independence and increase the risk of serious injury. The accumulation of iron in muscle may be a significant factor in the development of sarcopenia. This work is relevant to public health in its aims to uncover the relation between muscle iron changes and sarcopenia so that future studies can be implemented with the objective of improving muscle quality and function of elderly individuals.