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

基本信息

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
项目类别：
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

项目摘要

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.

总体抽象。计划项目（P01）赠款的目标是提供有关该计划的急需信息与年龄相关的骨骼肌肌肉质量和力量丧失的机制，通常称为 Sarcopenia。我们团队的研究表明，铜锌超氧化物歧化酶的小鼠（Cuznsod，Cuznsod， SOD1KO小鼠）在整个早期的肌肉结构和功能中表现出逐渐下降到中期，SOD1KO小鼠类似于非常古老的野生型小鼠。慢性氧化应激与肌肉减少症之间的联系。衰老和SOD1KO小鼠是神经肌肉连接（NMJ）的变性。肌肉减少症的突触后因素和突触后因素，我们开发了具有神经或肌肉特异性的新小鼠模型 SOD1或SOD1的缺乏恢复了SOD1KO小鼠的神经元。调查结果：1派对SOD1KO小鼠Sod1ko小鼠的Cuznsod on隆，早产的萎缩，仅在神经元中的cuznsod的2缺陷造成的严重程度不如SOD1KO小鼠观察到的严重程度，而小鼠的严重程度则不如观察到的。仅在肌肉中的三杆cuznsod导致萎缩无力。由氧化的氧化还原状态引起的神经元缺陷在肌肉减少症中至关重要，但在任何一个中，SOD1的修订单独单独神经元或骨骼肌就会枯竭SOD1KO小鼠的表型，这表明是一种互动肌肉和神经组织之间的影响。对于肌肉减少症。由于SOD1缺乏或衰老，启动NMJ会导致肌肉肌肉功能障碍（2）在肌肉能够维持方形功能的能力的情况下，随之而来的变化 ROS，钙和/或炎症将反馈以进一步损害NMJ的维持在Atgented Aim中的这一假设将决定1。氧化还原稳态改变的影响在NMJ形成和功能的运动神经元中，2。肌肉线粒体（MTROS）是诱导肌肉减少症的必要条件，3。肌肉mtros的作用，钙，弱点和肌肉纤维损失中的炎症。由行政和动物资源核心支持的协同项目，他们取得了成功这种交互式P01依赖于共享的动物模型，频繁的接触和高度协作科学。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Skeletal muscle transcriptomics identifies common pathways in nerve crush injury and ageing.

DOI：
10.1186/s13395-021-00283-4
发表时间：
2022-01-29
期刊：
Skeletal muscle
影响因子：
4.9
作者：
Staunton CA;Owen ED;Hemmings K;Vasilaki A;McArdle A;Barrett-Jolley R;Jackson MJ
通讯作者：
Jackson MJ

Emerging molecular mediators and targets for age-related skeletal muscle atrophy.

DOI：
10.1016/j.trsl.2020.03.001
发表时间：
2020-07
期刊：
Translational research : the journal of laboratory and clinical medicine
影响因子：
0
作者：
Brown LA;Guzman SD;Brooks SV
通讯作者：
Brooks SV

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。

DOI：
10.1523/eneuro.0086-22.2023
发表时间：
2023
期刊：
eNeuro
影响因子：
3.4
作者：
Pollock N
通讯作者：
Pollock N

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

DOI：
10.1093/ageing/afy143
发表时间：
2018-09-01
期刊：
Age and ageing
影响因子：
6.7
作者：
Kemp GJ;Birrell F;Clegg PD;Cuthbertson DJ;De Vito G;van Dieën JH;Del Din S;Eastell R;Garnero P;Goljanek-Whysall K;Hackl M;Hodgson R;Jackson MJ;Lord S;Mazzà C;McArdle A;McCloskey EV;Narici M;Peffers MJ;Schiaffino S;Mathers JC
通讯作者：
Mathers JC

Redox responses are preserved across muscle fibres with differential susceptibility to aging.

氧化还原反应在对衰老的敏感性不同的肌肉纤维中得以保留。

DOI：
10.1016/j.jprot.2018.02.015
发表时间：
2018
期刊：
Journal of proteomics
影响因子：
3.3
作者：
Smith,NeilT;Soriano-Arroquia,Ana;Goljanek-Whysall,Katarzyna;Jackson,MalcolmJ;McDonagh,Brian
通讯作者：
McDonagh,Brian