Innervation and neuromuscular control in ageing skeletal muscle

Abstract

Changes in the neuromuscular system affecting the ageing motor unit manifest structurally as a reduction in motor unit number secondary to motor neuron loss; fibre type grouping due to repeating cycles of denervation-reinnervation; and instability of the neuromuscular junction that may be due to either or both of a gradual perturbation in postsynaptic signalling mechanisms necessary for maintenance of the endplate acetylcholine receptor clusters or a sudden process involving motor neuron death or traumatic injury to the muscle fibre. Functionally, these changes manifest as a reduction in strength and coordination that precedes a loss in muscle mass and contributes to impairments in fatigue. Regular muscle activation in postural muscles or through habitual physical activity can attenuate some of these structural and functional changes up to a point along the ageing continuum. On the other hand, regular muscle activation in advanced age (>75 years) loses its efficacy, and at least in rodents may exacerbate age-related motor neuron death. Transgenic mouse studies aimed at identifying potential mechanisms of motor unit disruptions in ageing muscle are not conclusive due to many different mechanisms converging on similar motor unit alterations, many of which phenocopy ageing muscle. Longitudinal studies of ageing models and humans will help clarify the cause and effect relationships and thus, identify relevant therapeutic targets to better preserve muscle function across the lifespan.

Figure 1. Morphological impact of motor unit alterations in aging muscle

Young adulthood is characterized by an intermingling of fibres belonging to different motor units. This yields a mosaic distribution of fibre types when muscle fibres are viewed in cross‐section. Adulthood to old age is characterized by repeating cycles of denervation–‐reinnervation that result in fibres of the same type being beside one another (fibre type grouping) when viewed in cross‐section. Very old age is characterized by increasing frequency of axonal degeneration and/or motor neuron death leading to grouped fibre atrophy when viewed in cross‐section.

Figure 2. The maintenance of the adult neuromuscular junction depends upon several proteins

Neural agrin released from the terminal motor neurons activates muscle‐specific kinase (MuSK) which in turn recruits rapsyn to the subsynaptic domain where it acts in conjunction with protein kinase A R1 (PKAR1) and myosin Va (Va) to anchor the acetylcholine receptors (AChR) to the cytoskeleton. This signalling network thus ensures that the terminal axons of the motor neuron directly oppose the postsynaptic membrane acetylcholine receptors to maintain a functional synapse. Note that at the neuromuscular junction agrin is inactivated by the endogenous protease, neurotryspin.