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Faster, higher, farther: outpacing age‐related motor neuron losses

Advancing age results in inevitable decline of physiological functions, but individuals can display remarkable variability between chronological and biological age. In an article in this issue of The Journal of Physiology, Sonjak and colleagues (2019) compared muscle biopsy features of denervation and reinnervation in world-class women masters athletes, as a model group of high-functioning agers, to groups of physically frail/pre-frail older women and young, inactive women. Physical frailty is a geriatric syndrome associated with exacerbated or accelerated impairment of physical function that is characterized by a mutually exacerbating cycle of negative energy balance, sarcopenia (loss of muscle mass), and diminished strength and tolerance for exertion. In recent years, the role of neurological degeneration, such as motor neuron loss, has increasingly been considered in the pathogenesis of muscle wasting and weakness. While there is little doubt that ageing is associated with losses of motor neurons and motor units, it remains uncertain if motor neuron losses contribute to an individual’s risk for developing muscle wasting, weakness or physical frailty. Sonjak and colleagues used a sophisticated approach to analyse muscle biopsy tissue to shed additional light on the relationships between age, physical frailty, physical performance and muscle health in older women. Vastus lateralis muscle biopsies were obtained from young inactive women, pre-frail or frail older women, and world class octogenarian women masters athletes who were ranked in the top five in the world in their respective events (4 sprint/ power and 3 endurance athletes). Biopsies were compared to investigate features of denervation, reinnervation and molecular signalling for remodelling of the neuromuscular junction. The pre-frailty/frailty group was defined based on the Fried criteria of unintended weight loss, exhaustion, weakness, slow gait speed and low physical activity. From these investigations, the older women demonstrated clear evidence of denervation as compared to the young women based on features of increased fibre type grouping and pyknotic nuclei. Denervation was noted in aged women irrespective of athletic background and activity levels suggesting that losses of motor neurons and motor unit numbers in older women may not be overtly modified by athletic and training history. Interestingly, reinnervation capacity and sufficiency, based on features of increased type I fibre type grouping and larger fibre group sizes, were increased in the world-class masters athletes. The authors also showed that fibroblast growth factor binding protein 1 (FGFBP1), a cytokine important for reinnervation, was increased in the older masters athletes compared with both the frail/pre-frail older women and the younger inactive women. Together this work suggests that remodelling of motor neuron connectivity at the neuromuscular junction may be an important driver of successful ageing and maintenance of muscle function. The findings of Sonjak and colleagues suggest that activity level may not prevent denervation during ageing, but since extent of motor neuron losses cannot be quantified via muscle biopsies a protective but partial effect on motor neuron losses (and denervation) cannot be excluded. Prior studies, including a study by Power and colleagues that included the world-class master participants of the present study, have shown that motor unit losses are less in high-level, competitive masters athletes but other studies have shown conflicting findings (Power et al. 2010, 2016; Piasecki et al. 2016). While denervation changes, consistent with motor neuron losses, were noted in both groups of older women in the current work, biopsies from world-class masters athletes showed findings of improved reinnervation. So is improved reinnervation related to genetic, environmental, or behavioural (e.g. training) influences, or a combination of factors? Unfortunately, separating the influence of exercise and intrinsic ageing biology is difficult and was beyond the scope of Sonjak and colleagues’ work. Interestingly, Mosole and colleagues have also shown findings of increased fibre type grouping in high functioning older adults with long-term high activity levels, but not necessarily classified as world-class athletes, compared with sedentary older adults (Mosole et al. 2014). Understanding the intrinsic and extrinsic factors that contribute to successful ageing and maintained neuromuscular function carries huge potential for reduction of healthcare needs and costs on society. Most of the therapeutic development efforts for sarcopenia have focused primarily on methods of increasing muscle mass, and in clinical trials these strategies have resulted in modest if not disappointing results (Becker et al. 2015). Future investigation is needed to understand if reinnervation capacity can be harnessed to lessen the impact of sarcopenia and physical frailty. It is important to keep in mind that associations between competitive and physical training history, physical prowess and neuromuscular health may not necessarily represent causation. Future longitudinal investigations are needed to address causation. Additional investigations are needed to explore cytokine signalling, such as FGFBP1, to understand if this signalling is directly related to exercise or other intrinsic or extrinsic factors related to the competitive behaviours of the world class women and whether these might be potential therapeutic targets for development. Lastly, we need to better understand how to optimize exercise for the promotion of lifelong neuromuscular health. For instance, is one type of exercise training paradigm better than others (e.g. endurance vs. sprint/power training)? Due to limited sample size, the current study did not compare muscle biopsies between different athletic events. Often the most successful athletes at high level masters competitions were not necessarily competitive or even