Denervation of small numbers of fibres during ageing leads to dysregulation of ROS and functional changes in whole skeletal muscles

衰老过程中少量纤维的去神经支配会导致 ROS 失调和整个骨骼肌的功能变化

• 批准号: BB/K003860/1
• 负责人: Malcolm Jackson
• 金额: $ 45.5万
• 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: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FK003860%2F1
• 关键词: Denervation; small; numbers; fibres; during

As we age our muscle become smaller and weaker and the reduced muscle function can eventually contribute to frailty and poor quality of life. These changes occur partly because we lose some of the muscle cells (called muscle fibres) as we age, but also the muscle we retain is weak, does not respond well to exercise or training and releases pro-inflammatory compounds that make it more sensitive to damage. 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. We believe that as the muscle fibres and motor nerves die, they release a highly reactive molecule (hydrogen peroxide) that affects the function of the neighbouring muscle fibres and makes them weak, prevents them from responding well to exercise or training and causes them to release pro-inflammatory molecules that make them more sensitive to damage.This possibility will be tested using a mouse model in which a branch of one nerve that innervates a small portion of a muscle in the mouse limb will be cut under anaesthetic to induce denervation of a small number of muscle fibres embedded within a large number of intact innervated fibres. This will not significantly affect muscle function and mobility in the mouse, but will allow us to look at the effects of denervation of a small number of fibres on the neighbouring innervated fibres as a mimic of what occurs during ageing. The effect of this denervation of a small number of fibres on the force generation by the adjacent intact fibres, their ability to adapt following contractions and their release of pro-inflammatory compounds will be examined. The possibility that these changes are mediated by hydrogen peroxide released from the denervated fibres will also be examined.Completion of these studies will provide further information on the mechanisms underlying muscle weakness during ageing and potentially provide indicators of the type of therapeutic interventions that may help preserve muscle function during ageing.

随着年龄的增长，我们的肌肉变得越来越小，肌肉功能降低最终会导致脆弱和生活质量差。这些变化的发生部分是因为随着年龄的增长，我们失去了一些肌肉细胞（称为肌肉纤维），但是我们保留的肌肉也很弱，对运动或训练的反应不佳，并且释放了促炎性化合物，从而使其对损害更加敏感。目前尚不清楚肌肉纤维在衰老过程中如何损失，但是当这些纤维死亡时，通常控制其活性的运动神经也会丢失。 We believe that as the muscle fibres and motor nerves die, they release a highly reactive molecule (hydrogen peroxide) that affects the function of the neighbouring muscle fibres and makes them weak, prevents them from responding well to exercise or training and causes them to release pro-inflammatory molecules that make them more sensitive to damage.This possibility will be tested using a mouse model in which a branch of one nerve that innervates a small portion of a muscle在小鼠中，将在麻醉下切割小鼠的肢体，以诱导少量嵌入大量完整神经支配纤维中的少数肌肉纤维的神经化。这不会显着影响小鼠中的肌肉功能和迁移率，但会使我们能够查看少数纤维对相邻神经支配的纤维的神经作用，以模仿衰老过程中发生的情况。将检查少数纤维对相邻完整纤维产生力产生的影响，将检查它们在收缩后适应的能力及其释放促炎化合物的能力。这些变化的可能性是由从不死的纤维中释放出来的过氧化氢介导的。这些研究的整体研究将提供有关衰老过程中肌肉无力的机制的进一步信息，并有可能提供治疗干预措施的指标，以帮助可以在衰老过程中保留肌肉功能。

项目成果

Neuron specific reduction in CuZnSOD is not sufficient to initiate a full sarcopenia phenotype.

• DOI: 10.1016/j.redox.2015.04.005
• 发表时间: 2015-08
• 期刊: REDOX BIOLOGY
• 影响因子: 11.4
• 作者: Sataranatarajan, Kavithalakshmi;Qaisar, Rizwan;Davis, Carol;Sakellariou, Giorgos K.;Vasilaki, Aphrodite;Zhang, Yiqiang;Liu, Yuhong;Bhaskaran, Shylesh;McArdle, Anne;Jackson, Malcolm;Brooks, Susan V.;Richardson, Arlan;Van Remmen, Holly
• 通讯作者: Van Remmen, Holly

Low protein intake compromises the recovery of lactation-induced bone loss in female mouse dams without affecting skeletal muscles

• DOI: 10.1101/2020.05.02.073759
• 发表时间: 2020-05
• 期刊: bioRxiv
• 作者: I. Kanakis;Moussira Alameddine;M. Scalabrin;R. J. van ‘t Hof;T. Liloglou;S. Ozanne;K. Goljanek‐Whysall;A. Vasilaki

Mechanistic models to guide redox investigations and interventions in musculoskeletal ageing.

指导肌肉骨骼衰老的氧化还原研究和干预的机制模型。

• DOI: 10.1016/j.freeradbiomed.2020.01.020
• 发表时间: 2020
• 期刊: Free radical biology & medicine
• 影响因子: 7.4
• 作者: Jackson MJ

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

Denervated muscle fibers induce mitochondrial peroxide generation in neighboring innervated fibers: Role in muscle aging.

• DOI: 10.1016/j.freeradbiomed.2017.07.017
• 发表时间: 2017-11
• 期刊: Free radical biology & medicine
• 影响因子: 7.4
• 作者: Pollock N;Staunton CA;Vasilaki A;McArdle A;Jackson MJ
• 通讯作者: Jackson MJ