Molecular Mechanisms of Neuromuscular Interactions Underlying Age-Related Atrophy

年龄相关性萎缩的神经肌肉相互作用的分子机制

• 批准号: 9920073
• 负责人: Susan V Brooks
• 金额: $ 166.35万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920073
• 关键词: Address; Age; Aging; Animal Model; Atrophic; Back; Calcium; Chronic; Data; Defect; Denervation; Development; Distal; Effectiveness; Elderly; Etiology; Financial cost; Future; Generations; Goals; Grant; Homeostasis; Impairment; Inflammation; Intervention; Knowledge; Leadership; Life; Link; Maintenance; Mitochondria; Modeling; Molecular; Motor Neurons; Mus; Muscle; Muscle Fibers; Muscle Mitochondria; Muscle Weakness; Muscle function; Muscular Atrophy; Nerve; Neural Conduction; Neuromuscular Junction; Neurons; Organism; Oxidation-Reduction; Oxidative Stress; Oxides; Pathway interactions; Phenotype; Play; Process; Production; Public Health; Quality of life; Reactive Oxygen Species; Regulation; Role; Science; Skeletal Muscle; Synapses; System; Testing; Tissues; Wild Type Mouse; age related; age-related muscle loss; animal resource; antioxidant enzyme; copper zinc superoxide dismutase; dietary restriction; disability; effective intervention; emerging adult; frailty; insight; middle age; mitochondrial dysfunction; mouse model; muscle form; muscle strength; muscular structure; neuromuscular; neuromuscular system; normal aging; novel; premature; prevent; programs; relating to nervous system; sarcopenia; skeletal muscle wasting; societal costs; success; superoxide dismutase 1

OVERALL ABSTRACT. The goal of this Program Project (P01) Grant is to provide much needed information regarding the mechanisms underlying age-associated loss of skeletal muscle mass and strength, often referred to as sarcopenia. Studies from our team show that mice deficient in copper zinc superoxide dismutase (CuZnSOD, Sod1KO mice) display progressive declines in muscle structure and function throughout early adulthood, such that by middle age the Sod1KO mice resemble very old wild type mice. These findings support a mechanistic link between chronic oxidative stress and sarcopenia. A key feature of the initiation of muscle declines with aging and in Sod1KO mice is the degeneration of neuromuscular junctions (NMJs). To probe the importance of pre- and post-synaptic factors in sarcopenia, we developed new mouse models with nerve- or muscle-specific deficiency of Sod1 or with Sod1 restored in neurons of Sod1KO mice. These mice have produced several key findings: 1-partial rescue of CuZnSOD only in neurons of Sod1KO mice prevented premature muscle atrophy, 2-deficiency of CuZnSOD only in neurons caused less severe atrophy than is observed in Sod1KO mice, and 3-lack of CuZnSOD only in muscle resulted in weakness without atrophy. These data indicate that motor neuron deficits arising from an oxidized redox status are critical in sarcopenia, but reduction of Sod1 in either neurons or skeletal muscle alone does not replicate the phenotype of Sod1KO mice, suggesting an interactive effect between both muscle and neural tissues. Thus, our objective is to critically test this “two-hit” mechanism for sarcopenia. We hypothesize that (1) defects in neuronal function arising from altered redox homeostasis, due to Sod1 deficiency or aging, initiate disruption of NMJs resulting in muscle mitochondrial dysfunction; and (2) under circumstances of impaired ability of muscles to maintain mitochondrial function, resultant changes in ROS, calcium, and/or inflammation will feed back to further impair maintenance of the NMJ. We will address this hypothesis in a set of highly integrated Aims that will determine 1. the impact of altered redox homeostasis in motor neurons on NMJ formation and function, 2. whether NMJ degeneration and increased ROS generation by muscle mitochondria (mtROS) are necessary to induce sarcopenia, and 3. the role of muscle mtROS, calcium, and inflammation in the weakness and muscle fiber loss. We will achieve these Aims through three synergistic Projects supported by Administrative and Animal Resource Cores that are key to the success of this interactive P01 that relies on shared animal models, frequent contact, and highly collaborative science.

总体摘要。 该计划项目 (P01) 赠款的目标是提供有关 与年龄相关的骨骼肌质量和力量损失的机制，通常称为 我们团队的研究表明，缺乏铜锌超氧化物歧化酶（CuZnSOD， Sod1KO 小鼠）在整个成年早期表现出肌肉结构和功能的逐渐衰退，例如 到了中年，Sod1KO 小鼠与非常老的野生型小鼠相似。这些发现支持了一种机制。 慢性氧化应激与肌肉减少症之间的联系是肌肉衰退的一个关键特征。 衰老和 Sod1KO 小鼠中神经肌肉接头（NMJ）的退化是探讨其重要性的。 针对肌肉减少症的突触前和突触后因素，我们开发了具有神经或肌肉特异性的新小鼠模型 Sod1KO 小鼠神经元中缺乏 Sod1 或恢复了 Sod1 这些小鼠产生了几个钥匙。 研究结果：1-仅在 Sod1KO 小鼠的神经元中部分挽救 CuZnSOD 可防止过早肌肉萎缩， 2-CuZnSOD 缺陷仅在神经元中引起的萎缩程度比在 Sod1KO 小鼠中观察到的要轻，并且 3-仅肌肉中缺乏CuZnSOD导致无力而不萎缩。这些数据表明运动能力。 氧化还原状态引起的神经元缺陷对于肌少症至关重要，但无论是哪种情况，Sod1 的减少都对肌少症至关重要。 单独的神经元或骨骼肌不能复制 Sod1KO 小鼠的表型，这表明交互作用 因此，我们的目标是严格测试这种“两次打击”机制。 对于肌肉减少症，我们遇到了（1）氧化还原稳态改变引起的神经功能缺陷， 由于 Sod1 缺乏或衰老，导致 NMJ 破坏，导致肌肉线粒体功能障碍；以及 (2)在肌肉维持线粒体功能的能力受损的情况下，所导致的变化 ROS、钙和/或炎症会反馈进一步损害 NMJ 的维持，我们将解决这一问题。 这一假设在一组高度综合的目标中，将确定 1. 氧化还原稳态改变的影响 运动神经元对NMJ形成和功能的影响，2. NMJ是否退化和ROS生成增加 肌肉线粒体 (mtROS) 是诱发肌肉减少症所必需的，并且 3. 肌肉 mtROS 的作用， 钙、虚弱和肌肉纤维损失的炎症我们将通过三个目标来实现这些目标。 由行政和动物资源核心支持的协同项目是成功的关键 这个交互式 P01 依赖于共享的动物模型、频繁的接触和高度协作的科学。

项目成果

Molecular changes associated with spinal cord aging.

与脊髓衰老相关的分子变化。

• 发表时间: 2020
• 影响因子: 5.6
• 作者: Piekarz, Katarzyna M;Bhaskaran, Shylesh;Sataranatarajan, Kavithalakshmi;Street, Kaitlyn;Premkumar, Pavithra;Saunders, Debra;Zalles, Michelle;Gulej, Rafal;Khademi, Shadi;Laurin, Jaime;Peelor, Rick;Miller, Benjamin F;Towner, Rheal;Van Remmen, H
• 通讯作者: Van Remmen, H

Myeloid Cell Responses to Contraction-induced Injury Differ in Muscles of Young and Old Mice.

年轻和年老小鼠肌肉中的骨髓细胞对收缩引起的损伤的反应不同。

• 发表时间: 2018
• 作者: Sloboda, Darcée D;Brown, Lemuel A;Brooks, Susan V
• 通讯作者: Brooks, Susan V

Deletion of Sod1 in Motor Neurons Exacerbates Age-Related Changes in Axons and Neuromuscular Junctions in Mice.

运动神经元中 Sod1 的缺失会加剧小鼠轴突和神经肌肉接头与年龄相关的变化。

• 发表时间: 2023-03
• 影响因子: 3.4
• 作者: Pollock, N;Macpherson, P C;Staunton, C A;Hemmings, K;Davis, C S;Owen, E D;Vasilaki, A;Van Remmen, H;Richardson, A;McArdle, A;Brooks, S V;Jackson, M J
• 通讯作者: Jackson, M J

Redox responses in skeletal muscle following denervation.

去神经支配后骨骼肌的氧化还原反应。

• 发表时间: 2019
• 影响因子: 11.4
• 作者: Scalabrin, Mattia;Pollock, Natalie;Staunton, Caroline A;Brooks, Susan V;McArdle, Anne;Jackson, Malcolm J;Vasilaki, Aphrodite
• 通讯作者: Vasilaki, Aphrodite

Developing a toolkit for the assessment and monitoring of musculoskeletal ageing.

开发用于评估和监测肌肉骨骼老化的工具包。

• 发表时间: 2018
• 影响因子: 6.7
• 作者: Kemp, Graham J;Birrell, Fraser;Clegg, Peter D;Cuthbertson, Daniel J;De Vito, Giuseppe;van Dieën, Jaap H;Del Din, Silvia;Eastell, Richard;Garnero, Patrick;Goljanek;Hackl, Matthias;Hodgson, Richard;Jackson, Malcolm J;Lord, Su
• 通讯作者: Lord, Su