Role of motor unit remodelling in age-related loss of skeletal muscle fibres.

运动单位重塑在与年龄相关的骨骼肌纤维损失中的作用。

• 批准号: MR/M012573/1
• 负责人: Malcolm Jackson
• 金额: $ 82.58万
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM012573%2F1
• 关键词: Role; motor; unit; remodelling; age

As we age our muscles become smaller and weaker and the reduced muscle function eventually contributes to frailty and poor quality of life. These changes occur partly because we lose a large proportion of the muscle cells (called muscle fibres), but also the muscle that we retain is weak. It is currently unknown how muscle fibres are lost during ageing, but when these fibres die, the motor nerves that normally control their activity are also lost. A fundamental question that has not yet been answered is whether the processes of ageing lead to a loss of proper functioning of nerves that causes loss of the muscle fibres activated by the nerve, or vice versa - that the primary changes in ageing are a loss of muscle that then causes loss of the nerve. This is a crucially important point since effective interventions to preserve muscle, or reverse the age-related changes in muscle function, will need to be targeted at the primary site of changes to be effective.We believe that, as we age, the way that nerves respond to damage changes such that eventually they become very slow to respond to everyday trauma experienced during activity and this leads to degeneration of the muscle fibres that the specific nerve branch supplies. Understanding whether the muscle fibres supplied by damaged nerve branches show the initial degenerative changes in ageing that eventually leads to loss of muscle fibres is crucial to finding ways of preventing muscle loss in ageing. Microscopes that detect very sensitive changes in nerve and muscle tissue have been developed that now allow us to examine the chronological changes that occur with ageing in individual motor nerves and the muscle fibres that they activate. This approach will be used to examine individual nerves and muscle of ageing mice, since these animals show a similar pattern of ageing and weakness to humans. The project will therefore use this form of microscopy (intra vital confocal microscopy) to determine whether all of the muscle fibres from old mice show age-related changes in several degenerative pathways, or whether only fibres where the specific nerve branch is disrupted show these changes. Data from this study should determine whether degeneration of the nerve is likely to be the key initial change during ageing. Finally we will undertake a study to attempt to identify factors that are released from muscle of young mice that stimulate rapid re-growth of nerve branches when these are damaged. Such substances are likely to be missing or modified in muscles from old mice, but replacement of them may potentially provide a means of helping preserve muscle during ageing.Completion of these studies will provide crucial information on the mechanisms underlying muscle weakness during ageing and provide indicators of the type of therapeutic interventions that may help preserve peripheral nerve and muscle function during ageing.

随着年龄的增长，我们的肌肉变得越来越小，越来越弱，肌肉功能的下降最终导致虚弱和生活质量低下。这些变化的发生部分是因为我们失去了大部分的肌肉细胞（称为肌纤维），但我们保留的肌肉也很弱。目前尚不清楚肌肉纤维在衰老过程中是如何丢失的，但当这些纤维死亡时，通常控制其活动的运动神经也会丢失。一个尚未回答的基本问题是，衰老过程是否会导致神经功能丧失，从而导致神经激活的肌肉纤维丧失，或者反之亦然-衰老的主要变化是肌肉的丧失，然后导致神经的丧失。这一点至关重要，因为保护肌肉或逆转与年龄相关的肌肉功能变化的有效干预措施需要针对变化的主要部位才能有效。我们认为，随着年龄的增长，神经对损伤的反应方式发生变化，最终它们对活动期间经历的日常创伤的反应变得非常缓慢，由特定的神经分支提供。了解受损神经分支提供的肌肉纤维是否显示出衰老过程中的最初退行性变化，最终导致肌肉纤维的损失，对于找到预防衰老过程中肌肉损失的方法至关重要。能够检测神经和肌肉组织中非常敏感的变化的显微镜已经被开发出来，现在可以让我们检查随着个体运动神经和它们激活的肌肉纤维的老化而发生的时间变化。这种方法将用于检查衰老小鼠的单个神经和肌肉，因为这些动物表现出与人类相似的衰老和虚弱模式。因此，该项目将使用这种形式的显微镜（活体共聚焦显微镜）来确定老年小鼠的所有肌纤维是否在几个退行性通路中显示出与年龄相关的变化，或者是否只有特定神经分支被破坏的纤维显示出这些变化。这项研究的数据应该确定神经退化是否可能是衰老过程中的关键初始变化。最后，我们将进行一项研究，试图确定从年轻小鼠的肌肉中释放的因子，这些因子在神经分支受损时刺激神经分支快速再生。这些物质很可能在老年小鼠的肌肉中缺失或改变，但它们的替代可能提供一种在衰老过程中帮助保护肌肉的方法。这些研究的完成将提供有关衰老过程中肌肉无力机制的关键信息，并提供可能有助于在衰老过程中保护外周神经和肌肉功能的治疗干预类型的指标。

项目成果

Neuron-specific deletion of CuZnSOD leads to an advanced sarcopenic phenotype in older mice.

• DOI: 10.1111/acel.13225
• 发表时间: 2020-10
• 期刊: Aging cell
• 影响因子: 7.8
• 作者: Bhaskaran S;Pollock N;C Macpherson P;Ahn B;Piekarz KM;Staunton CA;Brown JL;Qaisar R;Vasilaki A;Richardson A;McArdle A;Jackson MJ;Brooks SV;Van Remmen H
• 通讯作者: Van Remmen H

Deletion of Sod1 in motor neurons exacerbates age-related changes in axons and NMJs associated with premature muscle atrophy in aging mice

运动神经元中 Sod1 的缺失会加剧轴突和 NMJ 的年龄相关变化，这些变化与衰老小鼠的过早肌肉萎缩有关

• DOI: 10.1101/2022.01.27.477840
• 发表时间: 2022
• 作者: Pollock N

The role of attenuated redox and heat shock protein responses in the age-related decline in skeletal muscle mass and function.

• DOI: 10.1042/ebc20160088
• 发表时间: 2017-07
• 期刊: Essays in biochemistry
• 影响因子: 6.4
• 作者: A. Mcardle;M. Jackson

Redox Control of Signalling Responses to Contractile Activity and Ageing in Skeletal Muscle.

• DOI: 10.3390/cells11101698
• 发表时间: 2022-05-20
• 期刊: Cells
• 影响因子: 6

The Role of Eif6 in Skeletal Muscle Homeostasis Revealed by Endurance Training Co-expression Networks.

• DOI: 10.1016/j.celrep.2017.10.040
• 发表时间: 2017-11-07
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Clarke K;Ricciardi S;Pearson T;Bharudin I;Davidsen PK;Bonomo M;Brina D;Scagliola A;Simpson DM;Beynon RJ;Khanim F;Ankers J;Sarzynski MA;Ghosh S;Pisconti A;Rozman J;Hrabe de Angelis M;Bunce C;Stewart C;Egginton S;Caddick M;Jackson M;Bouchard C;Biffo S;Falciani F
• 通讯作者: Falciani F