p75 neurotrophin receptor preserves neuromuscular synapse stability and muscle strength during aging.

Age-related decline of the neuromuscular junction (NMJ), the peripheral synapse that controls muscle contraction, contributes to muscle weakness and impaired motor function in aging. The NMJ comprises a motor axon terminal, a skeletal muscle fibre, and terminal Schwann cells (tSC). Neurotrophin signalling is essential for mature NMJ organisation, with the p75 receptor acting as a key regulator of its morphology and function. However, the potential contribution of p75 to age-related NMJ decline remains unexplored. In this study, we used germline p75 knockout (p75⁻/⁻) mice to examine how the lifelong absence of p75 impacts NMJ stability and muscle function during aging through quantitative morphometric analyses, postsynaptic receptor dynamics, muscle histology, and functional strength testing. Although NMJ morphology was preserved, aged p75⁻/⁻ mice exhibited pronounced denervation and reduced tSC coverage, hallmarks of age-associated NMJ degeneration. Moreover, postsynaptic domains of aged p75⁻/⁻ mice displayed reduced stability of membrane-bound acetylcholine receptors. Glycolytic muscle fibres also showed signs of atrophy. Notably, aged p75⁻/⁻ mice exhibited a significant reduction in muscle strength compared with age-matched controls. Together, our findings are consistent with cumulative effects of persistent p75 deficiency on NMJ integrity and function during aging, supporting its potential relevance for interventions aimed at preventing age-associated neuromuscular decline.