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

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会导致身体虚弱和生活质量下降。发生这些变化的部分原因是，随着年龄的增长，我们失去了一些肌肉细胞（称为肌纤维），但我们保留的肌肉也很脆弱，对运动或训练反应不佳，会释放促炎化合物，使其对损伤更敏感。目前还不清楚肌肉纤维是如何在衰老过程中丢失的，但是当这些纤维死亡时，通常控制它们活动的运动神经也会丢失。我们认为，随着肌肉纤维和运动神经的死亡，它们会释放出一种高度反应性的分子（过氧化氢），这种分子会影响邻近肌肉纤维的功能，使它们变得虚弱，阻止它们对运动或训练做出良好的反应，并导致它们释放出促炎分子，使它们对损伤更敏感。这种可能性将通过小鼠模型进行测试。在小鼠模型中，在麻醉状态下，切断小鼠肢体中支配一小部分肌肉的神经分支，以诱导嵌入在大量完整的神经支配纤维中的少量肌肉纤维去神经支配。这不会显著影响老鼠的肌肉功能和活动能力，但会让我们看到少量纤维去神经支配对邻近神经支配纤维的影响，就像衰老过程中发生的模拟一样。少量纤维的去神经支配对相邻完整纤维产生的力的影响，它们在收缩后的适应能力和促炎化合物的释放将被检查。这些变化是由去神经纤维释放的过氧化氢介导的可能性也将被检查。这些研究的完成将提供有关衰老过程中肌肉无力机制的进一步信息，并可能提供有助于保持衰老过程中肌肉功能的治疗干预类型的指标。

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.