Neuromuscular plasticity with muscle disuse and sarcopenia

Background: The neuromuscular system demonstrates an exceptional level of plasticity. Motor units (MUs), the smallest functional components of the neuromuscular system, play a fundamental role in this remodelling. Using an integrative physiological approach, I exploited musculoskeletal imaging, muscle function testing and electrophysiological and molecular approaches to comprehensively gain deeper insights into the mechanisms underpinning the neuromuscular changes triggered by disuse and sarcopenia in humans. In order to achieve this goal, I structured my PhD project along with two original research articles and one review article. First Study: In this, 11 recreationally active young males took part into a 10-day ULLS intervention. ULLS was followed by 21 days of active recovery based on resistance exercises performed three times per week. Our findings supported previous observations suggesting that short-term disuse is associated with muscle atrophy and weakness at the whole muscle level, neuromuscular junction (NMJ) molecular instability and initial signs of myofibre denervation. Moreover, we showed that NMJ function remains stable following the 10 days of ULLS, highlighting its functional resilience. Decreased MU firing rates and increased MU potential complexity were also observed following unloading, possibly due to increased axonal damage and alterations in skeletal muscle ion channels dynamics. Finally, the active recovery period effectively restored most of these neuromuscular changes. Second Study – Literature review: Traditional severe disuse models do not accurately reproduce the effects of a sedentary lifestyle, an authentic pandemic of modern society. My second PhD article is a narrative review focusing on an experimental paradigm that mimics better sedentarism: step reduction. Analogues models of reduced physical activity have been proposed in rodents and are also discussed in the review. The existing body of literature demonstrates that these interventions of reduced physical activity, even of brief duration, can induce remarkable alterations in skeletal muscle health and metabolic function. These changes encompass reductions in muscle mass, muscle force, muscle protein synthesis, cardiorespiratory performance, endothelial function, and insulin sensitivity, while concurrently leading to increases in fat mass and inflammation. We provided a direct comparison of the pathophysiological impact of step reduction with other human models of disuse. Finally, methodological considerations, knowledge gaps and future directions for both animal and human models are also addressed in the review. Third Study: My final PhD article was focused on the investigation of the morphological, functional, electrophysiological and molecular alterations triggered by sarcopenia. In this cross-sectional study, we recruited 42 healthy young individuals (Y) and 88 older individuals. According to the guidelines of the EWGSOP2, 39 older individuals were non-sarcopenic, 31 pre-sarcopenic and 18 sarcopenic. As expected, sarcopenic individuals displayed an overall greater impairment in different domains of muscle function and physical performance, accompanied by more pronounced muscle wasting. NMJ stability and transmission, MU potential properties, MUs number, axonal damage and innervation profile were impaired in aged compared to young individuals. However, none of these parameters was further exacerbated in sarcopenic individuals compared to non-sarcopenic counterparts. It appears that these neuromuscular alterations occur before the development of overt sarcopenia, as they are evident in non-sarcopenic older individuals. Conclusion: Overall, the findings of this dissertation contributed to advancing the present knowledge on the neuromuscular system plasticity with disuse and sarcopenia, providing a useful basis for the development of effective countermeasures in these scenarios.