MTOR Signaling-Related MicroRNAs As Cardiac Hypertrophy Modulators In High- Volume Endurance Training: 213

Aerobic exercise training (ET) promotes cardiovascular adaptations, including physiological left ventricular hypertrophy (LVH), but not all mechanisms that underlie these changes are clear. PURPOSE: To elucidate the molecular mechanisms involved in high-volume ET-induced physiological LVH. METHODS: Eight-week old female Wistar rats were assigned to three groups: sedentary control (SC), trained protocol 1 (P1), and trained protocol 2 (P2). P1 consisted of 60 minutes/day of swimming, 5x/week, for 10 weeks. P2 consisted of the same protocol as P1 until the 8th week; in the 9th week, rats trained 2x/day, and in the 10th week, rats trained 3x/day. Structural and molecular parameters were evaluated in the heart. RESULTS: Trained groups demonstrated an enhanced VO2 Peak (P1: 29% and P2: 34%; p < 0.001), exercise tolerance (P1: 28%, p < 0.05; P2: 50%, p < 0.01), and LVH (P1: 14% and P2: 28%; p < 0.001) when compared to SC group. Exercise tolerance and LVH increase in a volume-dependent manner (p < 0.05). Furthermore, an increase of 50% (P1) and 48% (P2) in the miRNA-26a-5p levels was observed in the heart compared to SC (p < 0.05). In contrast, miRNA-16-5p was reduced by 31% (P1) and 63% (P2) compared to SC (p < 0.01). Additionally, the miRNA-16-5p knockdown increase 86% (p < 0.001) of the cardiomyocyte size in neonatal rat cardiomyocytes. Also, the miRNA-26a-5p overexpression increase 60% (p < 0.001) of the cardiomyocyte size in neonatal rat. These miRNAs were selected because of their relation to the mTOR signaling pathway using Diana Tolls bioinformatics website. The protein expression were increased more pronounced in P2, AKT increased 77% (P1) and 130% (P2), mTOR 65% (P1) and 75% (P2), p70S6k 30% (P2), and 4E-BP1 30% (P2). Nonetheless, GSK3β protein expression was reduced 22% (P1) and 20% (P2). All protein expression was compared to control (p < 0.05). CONCLUSION: In this study, ET reduced the miRNA-16-5p levels, consequently increasing the expression of the target genes Akt, mTOR, and p70S6k. ET also increased the miRNA-26a-5p levels, which then reduced the expression of the target gene GSK3β. Together, these changes contributed to the physiological LVH observed in high-volume training. Supported by FAPESP Grant: #2015/22814-5 and #2015/17275-8; CNPq Grant: #313479/2017-8; CAPES-PROEX Grant: #88887.484856/2020-00.