Motor unit loss and neuromuscular junction degeneration precede clinically diagnosed sarcopenia

Abstract

Background: Degeneration of motoneuron and neuromuscular junctions (NMJ) and loss of motor units (MUs) contribute to age-related muscle wasting and weakness, leading to sarcopenia. However, these features have not been adequately investigated in humans. This study aimed to compare neuromuscular system integrity and function across different stages of sarcopenia, with a particular focus on NMJ stability and MU properties. We hypothesized that progressive impairment of the neuromuscular system would be a hallmark of the progression of sarcopenia. Methods: We recruited 42 healthy young individuals (Y) (aged 25.98±4.6 yr; 57% females) and 88 older individuals (aged 75.9±4.7 yr; 55% females). The older group underwent a sarcopenia screening according to the revised guidelines of the European Working Group on Sarcopenia in Older People (EWGSOP2). In all groups, knee extensor muscle force was evaluated by isometric dynamometry, muscle size by ultrasound and MUP properties by intramuscular electromyography (iEMG). MU number estimate (iMUNE) was also obtained. Blood samples and muscle biopsies were collected to assess biomarkers of neuromuscular degeneration. Results: 39 older individuals were non-sarcopenic (NS), 31 pre-sarcopenic (PS) and 18 sarcopenic (S). A progressive decline in quadriceps force, cross-sectional area and appendicular lean mass was detected with the different stages of sarcopenia. Handgrip force and short physical performance battery (SPPB) scores were also progressively reduced. iEMG recordings showed increased near fiber segment jitter in NS, PS and S compared to the Y group, highlighting a decreased NMJ transmission stability. Elevated concentration of serum C-terminal agrin fragment and altered Cav3 protein expression further supported the finding of age-related NMJ instability in all the older groups. The iMUNE was lower in all older groups, confirming age-related loss of MUs. Motoneuron firing rate was decreased in S vs Y. Age-related increases in MU potential complexity were also observed. These observations were accompanied by increased muscle denervation and axonal damage, respectively, indicated by the increase in NCAM-positive fibres and the increase in serum concentration of neurofilament light chain. Notably, most of these MU and NMJ parameters did not differ in older individuals with or without sarcopenia. Conclusion: Alterations in MU properties, axonal damage, altered innervation profile and NMJ instability are signatures of neuromuscular system ageing. These neuromuscular impairments are accompanied by muscle atrophy and weakness, however, they appear to precede clinically diagnosed sarcopenia, as they are already detectable in older NS individuals. These are important parameters to monitor in order to counteract these impairments and slow down the onset and progression of sarcopenia. The present work was funded by the PRIN project ‘NeuAge’ (2017CBF8NJ_001) to MVN and MAP and the Milky Way Foundation, the Baxter Foundation and the Li Ka Shing Foundation to HMB. EM was supported by the Stanford Wu Tsai Human Performance Institute fellowship and Marie Skłodowska-Curie Actions postdoctoral fellowship. We also acknowledge co-funding from Next Generation EU to MVN, in the context of the National Recovery and Resilience Plan, Investment PE8 — Project Age-It: “Ageing Well in an Ageing Society”. This resource was co-financed by the Next Generation EU [DM 1557 11.10.2022]. The views and opinions expressed are only those of the authors and do not necessarily reflect those of the European Union or the European Commission. Neither the European Union nor the European Commission can be held responsible for them. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.