Key points Skeletal muscle size and strength decline in older age.The vastus lateralis, a large thigh muscle, undergoes extensive neuromuscular remodelling in healthy ageing, as characterized by a loss of motor neurons, enlargement of surviving motor units and instability of neuromuscular junction transmission.The loss of motor axons and changes to motor unit potential transmission precede a clinically‐relevant loss of muscle mass and function. AbstractThe anterior thigh muscles are particularly susceptible to muscle loss and weakness during ageing, although how this is associated with changes to neuromuscular structure and function in terms of motor unit (MU) number, size and MU potential (MUP) stability remains unclear. Intramuscular (I.M.) and surface electromyographic signals were recorded from the vastus lateralis (VL) during voluntary contractions held at 25% maximal knee extensor strength in 22 young (mean ± SD, 25.3 ± 4.8 years) and 20 physically active older men (71.4 ± 6.2 years). MUP size, firing rates, phases, turns and near fibre (NF) jiggle were determined and MU number estimates (MUNEs) were made by comparing average surface MUP with maximal electrically‐evoked compound muscle action potentials. Quadriceps cross‐sectional area was measured by magnetic resonance imaging. In total, 379 individual MUs were sampled in younger men and 346 in older men. Compared to the MU in younger participants, those in older participants had 8% lower firing rates and larger MUP size (+25%), as well as increased complexity, as indicated by phases (+13%), turns (+20%) and NF jiggle (+11%) (all P < 0.0005). The MUNE values (derived from the area of muscle in range of the surface‐electrode) in older participants were ∼70% of those in the young (P < 0.05). Taking into consideration the 30% smaller cross‐sectional area of the VL, the total number of MUs in the older muscles was between 50% and 60% lower compared to in young muscles (P < 0.0005). A large portion of the VL MU pool is lost in older men and those recruited during moderate intensity contractions were enlarged and less stable. These MU changes were evident before clinically relevant changes to muscle function were apparent; nevertheless, the changes in MU number and size are probably a prelude to future movement problems.

Voluntary control of skeletal muscle enables humans to interact with and manipulate the environment. Lower muscle mass, weakness and poor coordination are common complaints in older age and reduce physical capabilities. Attention has focused on ways of maintaining muscle size and strength by exercise, diet or hormone replacement. Without appropriate neural innervation, however, muscle cannot function. Emerging evidence points to a neural basis of muscle loss. Motor unit number estimates indicate that by age around 71 years, healthy older people have around 40 % fewer motor units. The surviving low- and moderate-threshold motor units recruited for moderate intensity contractions are enlarged by around 50 % and show increased fibre density, presumably due to collateral reinnervation of denervated fibres. Motor unit potentials show increased complexity and the stability of neuromuscular junction transmissions is decreased. The available evidence is limited by a lack of longitudinal studies, relatively small sample sizes, a tendency to examine the small peripheral muscles and relatively few investigations into the consequences of motor unit remodelling for muscle size and control of movements in older age. Loss of motor neurons and remodelling of surviving motor units constitutes the major change in ageing muscles and probably contributes to muscle loss and functional impairments. The deterioration and remodelling of motor units likely imposes constraints on the way in which the central nervous system controls movements.

Declining muscle mass and function is one of the main drivers of loss of independence in the elderly. Sarcopenia is associated with numerous cellular and endocrine perturbations, and it remains challenging to identify those changes that play a causal role and could serve as targets for therapeutic intervention. In this study, we uncovered a remarkable differential susceptibility of certain muscles to age-related decline. Aging rats specifically lose muscle mass and function in the hindlimbs, but not in the forelimbs. By performing a comprehensive comparative analysis of these muscles, we demonstrate that regional susceptibility to sarcopenia is dependent on neuromuscular junction fragmentation, loss of motoneuron innervation, and reduced excitability. Remarkably, muscle loss in elderly humans also differs in vastus lateralis and tibialis anterior muscles in direct relation to neuromuscular dysfunction. By comparing gene expression in susceptible and non-susceptible muscles, we identified a specific transcriptomic signature of neuromuscular impairment. Importantly, differential molecular profiling of the associated peripheral nerves revealed fundamental changes in cholesterol biosynthetic pathways. Altogether our results provide compelling evidence that susceptibility to sarcopenia is tightly linked to neuromuscular decline in rats and humans, and identify dysregulation of sterol metabolism in the peripheral nervous system as an early event in this process.

Key points The age‐related loss of muscle mass is related to the loss of innervating motor neurons and denervation of muscle fibres.Not all denervated muscle fibres are degraded; some may be reinnervated by an adjacent surviving neuron, which expands the innervating motor unit proportional to the numbers of fibres rescued.Enlarged motor units have larger motor unit potentials when measured using electrophysiological techniques.We recorded much larger motor unit potentials in relatively healthy older men compared to young men, but the older men with the smallest muscles (sarcopenia) had smaller motor unit potentials than healthy older men.These findings suggest that healthy older men reinnervate large numbers of muscle fibres to compensate for declining motor neuron numbers, but a failure to do so contributes to muscle loss in sarcopenic men. AbstractSarcopenia results from the progressive loss of skeletal muscle mass and reduced function in older age. It is likely to be associated with the well‐documented reduction of motor unit numbers innervating limb muscles and the increase in size of surviving motor units via reinnervation of denervated fibres. However, no evidence exists to confirm the extent of motor unit remodelling in sarcopenic individuals. The aim of the present study was to compare motor unit size and number between young (n = 48), non‐sarcopenic old (n = 13), pre‐sarcopenic (n = 53) and sarcopenic (n = 29) men. Motor unit potentials (MUPs) were isolated from intramuscular and surface EMG recordings. The motor unit numbers were reduced in all groups of old compared with young men (all P < 0.001). MUPs were higher in non‐sarcopenic and pre‐sarcopenic men compared with young men (P = 0.039 and 0.001 respectively), but not in the vastus lateralis of sarcopenic old (P = 0.485). The results suggest that extensive motor unit remodelling occurs relatively early during ageing, exceeds the loss of muscle mass and precedes sarcopenia. Reinnervation of denervated muscle fibres probably expands the motor unit size in the non‐sarcopenic and pre‐sarcopenic old, but not in the sarcopenic old. These findings suggest that a failure to expand the motor unit size distinguishes sarcopenic from pre‐sarcopenic muscles.

Muscle motor unit numbers decrease markedly in old age, while remaining motor units are enlarged and can have reduced neuromuscular junction transmission stability. However, it is possible that regular intense physical activity throughout life can attenuate this remodeling. The aim of this study was to compare the number, size, and neuromuscular junction transmission stability of tibialis anterior (TA) motor units in healthy young and older men with those of exceptionally active master runners. The distribution of motor unit potential (MUP) size was determined from intramuscular electromyographic signals recorded in healthy male Young (mean ± SD, 26 ± 5 years), Old (71 ± 4 years) and Master Athletes (69 ± 3 years). Relative differences between groups in numbers of motor units was assessed using two methods, one comparing MUP size and muscle cross‐sectional area (CSA) determined with MRI, the other comparing surface recorded MUPs with maximal compound muscle action potentials and commonly known as a “motor unit number estimate (MUNE)”. Near fiber (NF) jiggle was measured to assess neuromuscular junction transmission stability. TA CSA did not differ between groups. MUNE values for the Old and Master Athletes were 45% and 40%, respectively, of the Young. Intramuscular MUPs of Old and Master Athletes were 43% and 56% larger than Young. NF jiggle was slightly higher in the Master Athletes, with no difference between Young and Old. These results show substantial and similar motor unit loss and remodeling in Master Athletes and Old individuals compared with Young, which suggests that lifelong training does not attenuate the age‐related loss of motor units.