miR-320-3p regulates apelin and TGF-β/SMAD3 signaling in hypobaric hypoxia exposed rats to induce skeletal muscle atrophy

Abstract

Emerging research on microRNA has decoded its crucial role in gene regulation, development and diseases. Skeletal muscle atrophy is reported in several chronic diseases as well as prolonged stay at high altitude. miR-320-3p is reported to be upregulated in various chronic diseases including cancer, heart diseases, diabetes, and chronic kidney diseases. The present study evaluates the role of miR-320-3p expression in regulating apelin and its downstream signaling under hypobaric hypoxia (HH) at high altitude. The expression of miR-320-3p was found to be upregulated during 7days HH (7DHH) exposure at 25,000 ft as compared to control group. The targets for miR-320-3p were retrieved from miRWalk 3.0, TargetScan 8.0, miRTarBase 10.0 databases in Rattus norvegicus. Using in silico approach, 26 myokines were screened out of total 14,435 targets of rno-miR-320-3p and levels of few myokines were experimentally validated. The expression of apelin, decorin, osteocrin, meteorin-like myokines were found to be significantly decreased while myostatin was significantly increased during HH exposure as compared to control rats. Enhanced expression of Tgfb and p-Smad3 under 7DHH indicated activation of protein degradation pathways. Expression of Pgc1a and Nrf2, the critical regulators of mitochondrial biogenesis, were significantly decreased under HH. Thus, increased expression of miR-320-3p regulate apelin and modulate downstream signaling via attenuation of mitochondrial biogenesis and myogenesis. Hence, miR-320-3p and myokines play pivotal role to regulate skeletal muscle atrophy. Further research on potential targets of miR-320-3p regulating the muscle mass may lead to the development of novel therapeutics in personalized medicine to combat skeletal muscle diseases.

Keywords: Apelin; Atrophy; Skeletal muscle; Therapeutics; miR-320-3p; miRNA.