Neuromuscular deconditioning with disuse: should we live more on our nerves?

The physiological and pathophysiological changes caused by inactivity in humans and lower mammals have attracted the interest of scientists and health carers since the early 20s (Cuthbertson, 1929). Many disuse models have been used over the years to study the effects of inactivity: immobilization by casting, unilateral lower limb suspension (ULLS) and bed rest being the most popular. Some of these disuse models, head‐down bed rest and lower limb suspension, have been specifically developed to mimic the changes occurring with spaceflight. One of the most detrimental consequences of disuse in space and on Earth is muscle atrophy, which particularly affects the antigravity muscles. Data from several mid‐ (20–60 days) to long‐term (90–120 days) bed rest studies have enabled researchers to establish that muscle atrophy is a very rapid process; ∼10% after 7 days of bed rest, that proceeds with an exponential time course resulting in a loss of quadriceps muscle size of about 30% after 90–120 days. The time of onset of muscle atrophy, and in particular the mechanisms underlying this process, are less well known. The few existing studies have shown significant fibre atrophy, in association with a marked reduction in mechanosensitive FAK protein phosphorylation, within 3 days of ULLS (Flück et al. 2014), accompanied by early activation of proteolysis, as suggested by an increased expression of atrogin‐1 and MuRF‐1 (Suetta et al. 2012; Flück et al. 2014). This indication of early activation of muscle protein breakdown seems to precede a marked decline in muscle protein synthesis (∼50%) within 10 days of ULLS (De Boer et al. 2007).

Whereas these data confirmed the vulnerability of human skeletal muscle to disuse and provided fundamental knowledge on the time course of atrophy and the possible molecular and metabolic regulators of this process, little was known so far on the vulnerability of the neuromuscular system to disuse. In 2003, Deschenes and Wilson found signs of muscle denervation, evidenced by an increased expression of neural cell adhesion molecule (NCAM), in skeletal muscle of young and old rats after 4 weeks of hindlimb suspension (Deschenes & Wilson, 2003), and in humans Arentson‐Lantz et al. (2016) reported increased NCAM expression after 14 days of bed rest. The paper by Demangel et al. (2017), in this issue of The Journal of Physiology, now provides the unprecedented finding that signs of muscle denervation appear within 3 days of muscle disuse induced by dry immersion (DI), a similar but more drastic method of bed rest.

Notably, these authors also report significant whole muscle and fibre atrophy after the 3‐day DI, together with an increase in co‐expression of hybrid myosin heavy chains (MHCs). These findings are extremely noteworthy since they suggest that disuse atrophy may not only be mediated by lack of mechanical loading, but may also be accentuated by denervation of muscle fibres which start expressing NCAM, normally absent in adult muscle but typically expressed in denervated muscle. The finding of an increased proportion of hybrid fibres co‐expressing type I and type IIX MHC after bed rest, with fibre‐switching toward the fast‐type, seems indeed consistent with the hypothesis of early denervation, the extreme form of which is found in spinal cord injury (SCI) patients. In these patients a progressive decline in the proportion of slow MHC isoform and an increase in the proportion of fibres co‐expressing both the fast and slow MHC isoforms has been observed within less than 2 years post SCI. Caution, however, should be expressed when interpreting early changes in MHC composition: the rate of turnover of myosin is 0.02–0.04% h⁻¹, that is just 1% in 24–48 h. This suggests that the transition of fibre types (which involves the removal and substitution of significant quantities of myosin) is likely to take longer than 3 days.

Since healthy volunteers normally fully recover from periods of disuse, these findings emphasize the remarkable plasticity of the neuromuscular system to changes in chronic loading and suggest that inactivity impacts on neuromuscular integrity from the very early days of disuse.

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Competing interests

None declared.