Role of Pannexin 1 ATP-Permeable Channels in the Regulation of Signaling Pathways during Skeletal Muscle Unloading.

Ksenia A Zaripova,Svetlana P Belova,Tatiana Y Kostrominova,Ekaterina P Kalashnikova,Boris S Shenkman,Tatiana L Nemirovskaya

doi:10.3390/ijms221910444

Abstract

Skeletal muscle unloading results in atrophy. We hypothesized that pannexin 1 ATP-permeable channel (PANX1) is involved in the response of muscle to unloading. We tested this hypothesis by blocking PANX1, which regulates efflux of ATP from the cytoplasm. Rats were divided into six groups (eight rats each): non-treated control for 1 and 3 days of the experiments (1C and 3C, respectively), 1 and 3 days of hindlimb suspension (HS) with placebo (1H and 3H, respectively), and 1 and 3 days of HS with PANX1 inhibitor probenecid (PRB; 1HP and 3HP, respectively). When compared with 3C group there was a significant increase in ATP in soleus muscle of 3H and 3HP groups (32 and 51%, respectively, p < 0.05). When compared with 3H group, 3HP group had: (1) lower mRNA expression of E3 ligases MuRF1 and MAFbx (by 50 and 38% respectively, p < 0.05) and MYOG (by 34%, p < 0.05); (2) higher phosphorylation of p70S6k and p90RSK (by 51 and 35% respectively, p < 0.05); (3) lower levels of phosphorylated eEF2 (by 157%, p < 0.05); (4) higher level of phosphorylated GSK3β (by 189%, p < 0.05). In conclusion, PANX1 ATP-permeable channels are involved in the regulation of muscle atrophic processes by modulating expression of E3 ligases, and protein translation and elongation processes during unloading.

Highlights

During hypokinesia, skeletal muscle undergoes atrophy due to the disbalance between protein synthesis and protein degradation [1,2,3]
After one day of unloading there were no significant changes in soleus muscle weight between 1C, 1H, and 1HP groups (Table 1)
After three days of unloading, soleus muscle weight was significantly lower in both 3H and 3HP groups when compared with 3C (Table 1)

Summary

Introduction

Skeletal muscle undergoes atrophy due to the disbalance between protein synthesis and protein degradation [1,2,3]. It was previously reported that ten days of muscle unloading leads to the accumulation of high-energy phosphates (PCr) [6] and calcium ions [7,8,9] in muscle fibers. Pharmacologically-induced decrease in the levels of high-energy phosphates and calcium ions in unloaded skeletal muscle results in the decrease of both muscle atrophy and slow-to-fast fiber type switching in soleus muscle [6,9,11,12]. Previous studies showed that extracellular ATP is one of the major autocrine-paracrine regulators of cell signaling activated in response to diverse stimuli, including hormones, neurotransmitters, mechanical stimuli, and inflammation [13]. Extracellular ATP might be one of the major regulators of physiological processes activated in unloaded skeletal muscle, including changes in the gene expression patterns

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Conclusion