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

随着年龄的增长，我们的肌肉变得越来越小，越来越弱，肌肉功能的降低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我们失去了大部分肌肉细胞（称为肌纤维），但我们保留的肌肉也很脆弱。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。一个尚未得到回答的基本问题是，衰老的过程是否会导致神经正常功能的丧失，从而导致由神经激活的肌纤维的丧失，或者相反——衰老的主要变化是肌肉的丧失，然后导致神经的丧失。这是至关重要的一点，因为有效的干预措施，以保持肌肉，或逆转与年龄相关的肌肉功能变化，将需要针对变化的主要部位是有效的。我们认为，随着年龄的增长，神经对损伤的反应方式发生了变化，最终它们对日常活动中经历的创伤的反应变得非常缓慢，这导致了特定神经分支供应的肌肉纤维的退化。了解受损神经分支提供的肌纤维是否在衰老过程中表现出最初的退行性变化，最终导致肌纤维的损失，对于找到防止衰老过程中肌肉损失的方法至关重要。可以检测神经和肌肉组织中非常敏感的变化的显微镜已经发展出来，现在可以让我们检查随着年龄增长而发生的单个运动神经和它们激活的肌肉纤维的时间变化。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肉纤维是否在几种退行性途径中显示与年龄相关的变化，或者是否只有特定神经分支被破坏的纤维显示这些变化。这项研究的数据将确定神经退化是否可能是衰老过程中关键的初始变化。最后，我们将进行一项研究，试图确定从年轻小鼠肌肉中释放的因子，这些因子在神经分支受损时刺激神经分支的快速再生。这些物质很可能在老年小鼠的肌肉中缺失或改变，但替换它们可能会提供一种帮助在衰老过程中保持肌肉的方法。这些研究的完成将提供衰老过程中肌肉无力机制的重要信息，并提供可能有助于保护衰老过程中周围神经和肌肉功能的治疗干预类型的指标。

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.