Plantar mechanical stimulation attenuates protein synthesis decline in disused skeletal muscle via modulation of nitric oxide level

Abstract

Both research conducted under microgravity conditions and ground-based space analog studies have shown that air pump-based plantar mechanical stimulation (PMS) of cutaneous mechanoreceptors of the sole of the foot is able to increase neuromuscular activity in the musculature of the lower limbs. This type of stimulation is able to attenuate unloading-induced skeletal muscle atrophy and impaired muscle function. The aim of the present study was to evaluate the effects of PMS on anabolic signaling pathways in rat soleus muscle following 7-day hindlimb suspension (HS) and to elucidate if the effects of PMS on anabolic processes would be NO-dependent. The soles of the feet were stimulated with a frequency of 1-s inflation/1-s deflation with a total of 20 min followed by 10 min rest. This cycle was repeated for 4 h each day. We observed a decrease in the soleus muscle mass after 7-day HS, which was not prevented by PMS. We also observed a decrease in slow-type fiber cross-sectional area (CSA) by 56%, which significantly exceeded a decrease (–22%) in fast-type fiber CSA. PMS prevented a reduction in slow-twitch fiber CSA, but had no effect on fast-twitch fiber CSA. PMS prevented a 63% decrease in protein synthesis after 7-day HS as well as changes in several key anabolic signaling regulators, such as p70S6k, 4E-BP1, GSK3β, eEF-2, p90RSK. PMS also prevented a decrease in the markers of translational capacity (18S and 28S rRNA, c-myc, 45S pre-rRNA). Some effects of PMS on anabolic signaling were altered due to NO-synthase inhibitor (L-NAME) administration. Thus, PMS is able to partially prevent atrophic processes in rat soleus muscle during 7-day HS, affecting slow-type muscle fibers. This effect is mediated by alterations in anabolic signaling pathways and may depend on NO-synthase activity.

NOS‐dependent effects of plantar mechanical stimulation on mechanical characteristics and cytoskeletal proteins in rat soleus muscle during hindlimb suspension

“…42,43 In addition, this process depended on the level of nitric oxide in the soleus muscle. 43 The above studies support the idea that PMS can be involved in the regulation of myosin phenotype transformation and protein metabolism in rat postural muscle under unloading conditions. Thus, evidence suggests that the stimulation of the cutaneous mechanoreceptors of the feet during unloading conditions may help to preserve some cytoskeletal proteins and thereby intrinsic stiffness of soleus muscle fibers.…”

Effects of Various Muscle Disuse States and Countermeasures on Muscle Molecular Signaling

“…As early as at the 1st day of the hindlimb unloading of rodents, a significant decrease in the level of protein synthesis was observed in the soleus muscle [ 83 ]; at the same time, there was not yet any significant decrease in muscle mass observed. A reduced level of protein synthesis, determined using the SuNSET method, was also observed at later stages of hindlimb unloading (3rd, 7th, 14th days) [ 83 , 84 , 85 ]. A decrease in the level of protein synthesis assessed using radioactive labeling was observed after 3-, 4-, 7- and 28-day or hindlimb unloading of rodents [ 86 , 87 , 88 , 89 ].…”

“…Recent studies in our laboratory showed that nitric oxide plays an important role in the regulation of protein synthesis and GSK-3 activity, as well as the content of ribosomal RNA at later stages of hindlimb unloading (day 7) [ 85 ]. Mechanical stimulation of the feet support zones prevented a decrease in the content of 18S and 28S rRNA after 7 days of hindlimb unloading in rats due to nitric oxide production.…”

“…Mechanical stimulation of the feet support zones prevented a decrease in the content of 18S and 28S rRNA after 7 days of hindlimb unloading in rats due to nitric oxide production. It also partially prevented a decrease in protein synthesis, which suggests that a decrease in translational capacity under conditions of functional unloading may contribute in a decrease in protein synthesis and is apparently regulated by the level of nitric oxide in the myoplasm of the skeletal muscle [ 85 ]. It cannot be ruled out that the NO/GSK-3 (or NO/rRNA) signaling pathway contributes to a decrease in the level of protein synthesis at the earlier stages of hindlimb unloading, including the period of increased mTOR activity.…”

“…Studies in rats with mechanical stimulation of the feet support zones during hindlimb unloading showed that the restoration of support afferentation prevents a change in the pattern of myosin gene expression, a decrease in the level of PGC-1α expression and protein synthesis, an increase in ubiquitin ligase expression under conditions of 1 and 3 days of functional unloading, as well as preventing the atrophy of the soleus muscle [ 81 , 83 , 256 ]. Recent studies show that a key role in most of the countermeasure effects of support stimulation is played by the activity of neuronal NO synthase [ 85 , 152 ].…”