Iron Accumulation in Aging Skeletal Muscle

描述（由申请人提供）：随着年龄的增长发生的肌肉质量和质量下降，称为肌肉减少症，可严重限制功能能力，独立性，并导致生活质量下降。尽管已经取得了进展，以解开骨骼肌在衰老过程中发生的许多功能和表型的变化，问题仍然是关于触发这些适应的机制。我们的长期目标是了解导致肌肉减少症发展的因素，这些因素可能促进更有效的治疗干预，以预防或延迟与衰老相关的肌肉损失。我们的小组最近确定了老年骨骼肌中非血红素铁水平升高的发生，并提出了铁积累在肌肉减少症进展中的基本作用。骨骼肌铁状态的增龄相关增加可能是导致氧化应激和肌肉功能障碍发展的重要因素。目前的实验将利用公认的啮齿动物模型来描绘骨骼肌铁状态的时间过程和随着衰老发生的调节变化，并评估铁螯合疗法在减轻衰老相关的肌肉减少症中的功效。目的#1是评估衰老对骨骼肌中铁分布和铁积累进展的影响。这些实验将揭示总的，非血红素，和血红素铁分布在骨骼肌的过程中的老化过程。目的#2是描绘骨骼肌铁调节的衰老相关变化。阐明铁调节机制的时间响应将提供必要的洞察力的潜在因素，导致铁的积累。目的#3是确定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的发展的影响。我们将利用铁螯合剂吡哆醛异烟酰腙（PIH）的长期给药，以确定铁积累作为肌肉减少症发展中的一个因素的相对重要性。这些实验的结果将为铁在肌肉减少症的发展中的假定作用提供有价值的见解，这将为未来的RO1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。公共卫生相关性：肌肉质量和功能随着年龄增长而下降，称为肌肉减少症，是一种重要的健康相关问题，可能限制人的功能独立性并增加严重损伤的风险。铁在肌肉中的积累可能是肌肉减少症发生的一个重要因素。这项工作与公共卫生有关，其目的是揭示肌肉铁变化与肌肉减少症之间的关系，以便未来的研究可以实现改善老年人肌肉质量和功能的目标。

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.