Neuromuscular junction instability with inactivity: morphological and functional changes after 10 days of bed rest in older adults

The neuromuscular junction (NMJ) plays a key role in modulating muscle contraction, but the impact of short-term disuse on NMJ structure and function, particularly in older humans, remains unclear. This study aimed to investigate NMJ alterations following 10 days of horizontal bed rest in 10 older males (68.5 ± 2.6 years). Before and after bed rest, vastus lateralis muscle biopsies were obtained to evaluate NMJ morphology, intramuscular EMG (iEMG) was recorded to assess NMJ function and blood samples were collected to determine circulating C-terminal agrin fragment (CAF) concentration, a biomarker of NMJ remodelling. In a sub-cohort of six participants who had NMJs in both pre- and post-bed rest biopsies, we observed altered NMJ morphology, including reduced overlap between NMJ terminals, as well as increased endplate area and perimeter. CAF concentration was elevated after bed rest, suggesting ongoing NMJ remodelling. iEMG analysis showed increased motor unit potential complexity and reduced firing rate. In addition, we observed impaired NMJ transmission, inferred from increased near-fibre jiggle and segment jitter. These findings suggest that older male individuals are susceptible to NMJ remodelling and impaired transmission with short-term disuse, providing valuable insights into the morphological and functional consequences of inactivity in an ageing population. Our study highlights the importance of developing interventions for mitigating the detrimental consequences of inactivity on neuromuscular health in older adults, which they frequently experience following injury, trauma, illness or surgery. KEY POINTS: The neuromuscular junction (NMJ) is crucial for signal transmission between the motoneuron and skeletal muscle, and NMJ alterations are linked to several neuromuscular disorders, as well as ageing. However, the impact of disuse on the structural and functional integrity of the NMJ, particularly in older humans, is largely unknown. We used the bed rest model to study the impact of inactivity on NMJ morphology and function in older men. We hypothesised that a 10 day bed rest period would lead to alterations in NMJ morphology and transmission. We show that 10 days of bed rest were sufficient to induce marked alterations in NMJ morphology, associated with an impaired NMJ transmission and with changes in motor unit potential properties. These findings suggest that older male individuals are vulnerable to NMJ dysfunction in response to inactivity and emphasise the importance of maintaining an active lifestyle for preserving neuromuscular health with ageing.