Motor unit behaviour of the ageing human diaphragm: mid‐life crisis for the inspiratory pump?

Time and tide wait for no man (or woman! ) Decline in respiratory system performance within the boundaries of healthy ageing is well appreciated. Spirometric assessment reveals progressive decline in functional measures with advancing age associated with altered lung and airway mechanics. Performance can be further compromised in older persons by substantive increases in the work of breathing during exercise. Furthermore, a wealth of studies in animals have shown that ageing is associated with motor neuron loss and diaphragm muscle fibre atrophy (Fogarty et al. 2018), which serve to limit diaphragm peak force production, likely contributing to the recognized reduction in maximal inspiratory pressure-generating capacity in healthy older individuals. Deficits and compensation in the neural circuitry controlling respiratory muscles have been described. There is considerable interest in the mechanisms of intrinsic nervous system plasticity in response to physiological stressors including ageing, as well as pathophysiological processes associated with acute and chronic injury, and neurological and neuromuscular disease. Indeed, there is a growing interest in the design and implementation of rehabilitative strategies that strive to harness and protect compensatory neural mechanisms that limit respiratory insufficiency in affected states. In this issue of The Journal of Physiology, Nguyen et al. (2019) characterize motor unit behaviour of the costal diaphragm during quiet breathing, seeking to directly address if respiratory neural drive to the primary muscle of breathing is increased with advancing age, as suggested by the observation made by other investigators of elevated normalized crural diaphragm electromyogram activity in healthy older individuals (Jolley et al. 2009). In healthy young (23–26 years), middle-aged (43–55 years) and older (65–80 years) male and female participants, Nguyen et al. (2019) made direct recordings of hundreds of costal diaphragm motor units characterizing unitary behaviours, including firing frequencies and morphology of motor potentials (duration, amplitude, area, phases and turns) determined from multiple recording sites in each individual. The authors hypothesized that motor unit discharge frequency and motor unit potential area would increase with ageing. Increased motor unit discharge frequency in older individuals would be reflective of greater pre-motor activation of phrenic motor neurons, representing a compensatory response to aged diaphragm neuromuscular remodelling. During quiet breathing, diaphragm motor unit peak discharge frequency did not differ between age groups, averaging 14–15 Hz. Similarly, onset and offset discharge frequencies were equivalent. A difference in the discharge durations was evident between groups. In older persons compared with middle-aged and young, the onset of motor unit discharge was delayed and activity ended earlier in the respiratory cycle, most likely related to increased pulmonary compliance in older participants. The timings of multi-unit electromyogram recordings during quiet breathing were equivalent between the three groups, reflecting no difference in central respiratory control of phrenic motor neurons innervating the diaphragm. In respect of motor unit morphology, the amplitude of motor units was equivalent across the age groups, but duration was increased in middle-aged participants, and motor unit area was approximately doubled, both in middle-aged and in older participants compared with young participants without any difference in the number of phases or turns. Thus, contrary to expectation, there is no global increase in neural drive to the ageing diaphragm muscle, notwithstanding clear evidence of neurogenic changes in motor units, which appear in middle age. Diaphragm motor unit potentials were generally of greater area, which most likely is reflective of re-innervation of denervated muscle fibres by spared phrenic motor axons, a process that commonly gives rise to grouped muscle fibres, as described in aged mouse diaphragm (Greising et al. 2015). Because all assessments in the study by Nguyen et al. (2019) were performed during quiet breathing, the motor potentials classified were slow fatigue-resistant units contributing to low-force production by the diaphragm, which is wholly adequate for resting breathing and indeed a broad range of ventilatory behaviours. Thus a limitation of the study acknowledged by the authors is that high-force demand motor units were not characterized, such as those recruited in support of non-ventilatory behaviours such as loaded breaths, efforts against an occluded airway, or cough. It is established that there is preferential loss of fast type 2X/2B motor units in ageing and also in animal models of spinal cord injury, amyotrophic lateral sclerosis and muscular dystrophy. Thus, it remains necessary to characterize human diaphragm motor unit properties during high-force manoeuvres, notwithstanding the technical challenges posed by such an endeavour. It is plausible to consider that the full portfolio of adaptive and maladaptive phenotypes will be most evident in the large motor unit pools that are recruited during high-force manoeuvres of the diaphragm. We are left to consider the potentially troubling signs of aberrant motor unit form in the population supporting resting breathing, appearing as early as middle age. The observation adds to the compendium of physiological decline in the respiratory system that is apparent with advancing age. Given the primacy of the diaphragm in support of ventilation, the findings and considerations of Nguyen et al. (2019) suggest that a maladaptive makeover presents in mid-life reflecting vulnerability in the respiratory system, which rather worryingly can be rapidly and robustly compounded by injury and disease. However, it is worth considering too that the diaphragm may get by with a little help from its friends! For example, it was recently demonstrated that peak inspiratory