When motor unit expansion in ageing muscle fails, atrophy ensues

Skeletal muscle atrophy is a hallmark of advancing age that contributes to mobility impairment, physical frailty and increased morbidity in the elderly (Del Signore & Roubenoff, 2017). In addressing the likely causes of ageing muscle atrophy, decades of research has underscored the occurrence of repeating cycles of denervation–reinnervation for much of adult life, resulting in advanced age in the well‐known fibre type grouping phenomenon (Kanda & Hashizume, 1989; Lexell & Downham, 1991; Larsson, 1995) that is also seen in neuromuscular diseases involving denervation at much earlier ages such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and Charcot‐Marie Tooth (CMT) disease (Carpenter & Karpati, 2001). Indeed, neuromuscular junction alterations are a well‐known occurrence in ageing muscle (Jang & Van Remmen, 2010), with changes in neuromuscular junction morphology occurring well‐before muscle exhibits atrophy (Deschenes et al. 2010; Valdez et al. 2012). Whereas a recent study suggests neuromuscular junction alterations (e.g. fragmentation of the acetylcholine receptor cluster on the muscle fibre) do not occur with ageing in human muscle (Jones et al. 2017), the results of this recent study are confounded by the source material which largely came from the amputated limbs of individuals with a history of peripheral vascular disease, noting that ischaemia–reperfusion is known to cause neuromuscular junction degeneration (Tu et al. 2017; Wilson et al. 2018). Indeed, other studies of neuromuscular junction morphology with ageing in human skeletal muscle (Oda, 1984; Wokke et al. 1990) have observed similar fragmentation patterns to that seen in rodent models of ageing (Valdez et al. 2012).

Although neuromuscular junction degeneration is likely to be a key characteristic of ageing muscle that occurs sporadically for much of adult life, the slow progression of muscle atrophy prior to the eighth decade of life (Berger & Doherty, 2010) underscores the typically highly efficient reinnervation response following individual denervation events during this period. This notion is consistent with both genetic models of unstable neuromuscular junctions where muscle atrophy is often mild or non‐existent in young adult animals despite frequent denervation events (Kulakowski et al. 2011; Aare et al. 2016), and surgical denervation models showing that axonal sprouting rapidly and effectively reinnervates denervated muscle fibres in adult muscle (Hopkins & Slack, 1981). Indeed, it is this reinnervation of denervated muscle fibres by collateral sprouting of axons innervating fibres that are directly adjacent to the affected fibre that causes fibre type grouping and in turn results in an expansion of the size of individual motor units with ageing (Ling et al. 2009).

Importantly, the severe muscle loss in neuromuscular diseases such as ALS, SMA and CMT shows that the capacity for reinnervation is finite and when depleted leads to the accumulation of persistently denervated muscle fibres that are severely atrophied. Similarly, analyses in both human muscle biopsies (Spendiff et al. 2016) and rodent muscles (Rowan et al. 2011) reveals a marked accumulation of small angular fibres scattered amongst more normal sized fibres in advanced age, and it has been suggested that this reflects a failure of reinnervation which becomes the primary driver of an acceleration of muscle atrophy in advanced age (Rowan et al. 2012; Aare et al. 2016). Thus, maintenance of muscle mass with advancing age must be a function of the rate of motor unit loss and the capacity for reinnervation through collateral sprouting of the remaining motor neurons, wherein individuals who have greater motor neuron loss and/or lower capacity for reinnervation would have a greater loss of muscle mass with ageing.

Despite the evidence noted above, an understanding of how denervation relates to the development of muscle atrophy with ageing in humans has been slow to emerge. The article by Piasecki and colleagues (2018) in this issue of The Journal of Physiology, provides valuable new insights to this long‐standing question. Specifically, Piasecki and colleagues used electromyographic methods to evaluate the motor unit size by examining the area of the motor unit potential (MUP), and motor unit number in the vastus lateralis and tibialis anterior muscles of young adults (age: 26.6 ± 4.9 years; mean ± SD), old individuals with maintained muscle mass (68.4 ± 4.3 years), old individuals with borderline low muscle mass (72.6 ± 5.2 years) and old individuals with low muscle mass (74.3 ± 7.9 years). Muscle mass cut‐offs were defined on the basis of quadriceps cross‐sectional area and this corresponded with the quotient of appendicular lean mass measured by dual X‐ray absorptiometry (excluding the bone mineral content) and height, where individuals with mean values of 6.66 kg m⁻² were classified as having low muscle mass. Their results revealed that whereas individuals with normal muscle mass or borderline low muscle mass exhibited significantly larger MUPs (indicative of larger motor units) than young adults by 26% and 41%, respectively, old individuals with low muscle mass had smaller MUPs than old individuals with maintained or borderline muscle mass and similar values to young adults. Furthermore, the intramuscular motor unit number estimate (iMUNE) was lower in each of the old groups compared to young adult in both vastus lateralis and tibialis anterior muscles, and for the vastus lateralis muscle the iMUNE was lower in old individuals with borderline low muscle mass and low muscle mass than old individuals with maintained muscle mass. The implication of these results is that individuals with exacerbated muscle atrophy with ageing have a lesser ability to expand their motor units in response to loss of motor units, and at least in vastus lateralis muscle, a greater loss of motor units overall. Importantly, although the individuals with low muscle mass tended to be older than the other two old groups, the lack of expansion of the MUPs in this group relative to young adult suggests an intrinsically inferior capacity for reinnervating denervated muscle fibres and potentially a greater motor neuron loss characterizes individuals who have exacerbated muscle loss with ageing. This is the first study to make this observation and it supports the notion that future studies addressing the mechanisms regulating reinnervation capacity and motor neuron loss with ageing will be key in seeking to identify therapeutic targets for attenuating the loss of muscle mass and strength with ageing.

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Competing interests

The author has no conflicts of interest.

Funding

No funding was received for the writing of this article.