Resting in bed – how quickly does the muscle lose its nerve?

It has been known for decades, if not centuries, that skeletal muscle is a highly plastic tissue, which responds to various insults, like exercise, injury and physical inactivity, in a multitude of ways. Muscle inactivity, either forced by bed rest in relation to acute medical disease, trauma and surgery, or as a result of a sedentary lifestyle or functional decline in ageing individuals, causes a marked weakening of muscle strength and muscle mass, which in turn results in a deterioration of overall musculoskeletal function. Despite continuous efforts to understand and counteract loss of muscle function with muscle disuse, we do not fully understand the physiological mechanisms behind this. Joint immobilization, spaceflight, dry immersion and bed rest are some of the elegant models that are being deployed in humans to study the effects of reduced activity on skeletal muscle biology. In the present issue of The Journal of Physiology, Monti et al. (2021) used a bed rest model to document that specific force, defined as muscle force/ muscle cross section area, decreased by approximately 10% following a 10-day bed rest intervention in young healthy men (Monti et al. 2021), indicating an incongruent decline in muscle mass and function. To unravel the mechanisms behind this, they undertook extensive single muscle fibre experiments and investigated muscle innervation. After 10 days of bed rest, knee extension maximal voluntary contraction force was reduced by 14.3%, and explosive strength decreased by 22.8%. In contrast, the decline in muscle mass using magnetic resonance imaging and ultrasonography measurements only ranged from 3.3% to 5.8%. The interpolated twitch technique revealed that activation capacity was not altered, meaning that the decline in specific force could not be explained by a lack of effort, and therefore indicates that certain intrinsic changes relating to force generation or perhaps force transmission must have occurred. Alterations in the muscle's Ca2+-handling properties will inevitably affect muscle function, and this was also demonstrated, as they used caffeine to study sarcoplasmic reticulum Ca2+ dynamics. Specifically, they reported an increased threshold for calcium release from sarcoplasmic reticulum at moderate caffeine concentrations and a decrease in maximum Ca2+ availability in the sarcoplasmic reticulum following exposure to high caffeine concentrations. In turn, no changes were observed in single fibre mechanical properties or fibre-type composition, indicating that 10 days of inactivity is enough to induce a change in the molecular composition of the sarcoplasmic reticulum, as evidenced by alterations in SERCA, calsequestrin and ryanodine receptor protein or gene abundance. Muscle innervation status was assessed by: 1) immunohistochemistry, demonstrating that the number of neural cell adhesion molecule-expressing muscle fibres was increased following the bed rest, confirming earlier findings (Arentson-Lantz et al. 2016); 2) RNA sequencing, which, in relation to innervation status, revealed that HOMER2 gene expression, a molecule accumulating at the postsynaptic site of neuromuscular junctions, decreased, while the denervation responsive acetylcholine receptor α1 subunit gene expression increased, which we have also seen in skeletal muscle biopsies of healthy elderly individuals following a single bout of resistance exercise (Soendenbroe et al. 2020); 3) determination of a tentative biomarker measured in the circulation, called the C-terminal agrin fragment, that was found to increase following the intervention, supporting the findings on the protein and gene expression levels. Importantly, although first published more than 10 years ago (Reif et al. 2007), C-terminal agrin fragment is still largely untested in conjunction with muscle biopsy assessments, and the authors should be commended for their initiative which can hopefully spur additional research in this area. The study by Monti et al. (2021) provides mechanistic evidence relating to the inactivity-induced decline in specific force, but further research is required on this topic to reach any definitive general conclusion. Neuromuscular junctions, the sole source of efferent input to muscles, are highly dynamic structures with alterations in morphology and functional properties occurring within seconds (Mansilla et al. 2018). While it is likely that the cumulative effects of long periods of bed rest on neuromuscular junction destabilization will rapidly subside in young healthy individuals, the long-term effects on the potential for reinnervation in such individuals remains to be determined. However, failed reinnervation is a feature of both ageing and certain diseases, and it can be speculated that muscle-derived molecular signals in such individuals are less efficient at reinnervating muscle following bouts of inactivity. If this hypothesis holds true, then within the context of ageing, yearly declines in skeletal muscle function might be almost undetectable, whereas short-term periods of inactivity can have grave and long-lasting effects on muscle health. Future studies could evaluate the purported mechanistic underpinnings of inactivity-related musculoskeletal system deterioration also in other groups of subjects, like those vulnerable to frequent hospitalization due to chronic disease as well as elderly people with increasing sarcopenia and frailty. Insight into the effects of ageing and physical (in)activity on the neuromuscular interplay can serve as a prerequisite for the development of future preventive and treatment strategies regarding overall bodily function of the musculoskeletal system. No competing interests declared. C.S., A.L.M. and M.K. were responsible for the conception and design of the work, drafting the work and revising it critically for important intellectual content, and approving the final version submitted for publication. C.S., A.L.M. and M.K. agree to be accountable for all aspects of the work. No funding was received.