Exercise Training Prevents Skeletal Muscle Atrophy And Dysfunction In Hypertension Involving A Set Of MicroRNAs

Abstract

PURPOSE: Aerobic exercise training (ET) has been used as an important non-pharmacological treatment of hypertension. MicroRNAs (miRNAs) are a new class of gene regulators in which inhibit protein expression by base-pairing with the 3’ UTRs of mRNA targets. We evaluated the skeletal muscle miRNAs profile and their target genes involved in hypertension-associated muscle disorders and checked the therapeutic role of ET on these parameters. METHODS AND RESULTS: Spontaneously hypertensive rats (SHR) aged 6 months and their controls Wistar Kyoto (WKY) were assigned to 4 groups: SHR, trained SHR (SHR-T), WKY and trained WKY (WKY-T). Swimming ET consisted of 60 min of duration, 1x/day/10 weeks, with 4% body weight workload. SHR showed an increased in systolic blood pressure (207 ± 5.5 mmHg) compared to WKY (133 ± 3.9 mmHg) analyzed by tail-cuff system, with no changes in baseline heart rate. We observed a reduction in VO2 peak (WKY: 62 ± 1.5; SHR: 53 ± 2.5 mL.kg-1.min-1) accompanied by soleus muscle atrophy (cross-sectional area: fiber type I - WKY: 4039 ± 195; SHR: 2658 ± 53; type IIa - WKY: 2903 ± 182, SHR: 2050 ± 68; Intermediate - WKY: 2663 ± 136, SHR: 1967 ± 95 μm2), change in fiber type profile (type I - WKY: 92.7 ± 1.5; SHR: 77.5 ± 1.8; type IIa - WKY: 4.8 ± 1.5; SHR: 18.5 ± 1.4; Intermediate - WKY: 1.1 ± 0.2; SHR: 3.9 ± 0.4 %) and dysfunction (specific force evaluated in the organ bath- tetanus 80Hz: WKY: 10.9 ± 0.3; SHR: 7.8 ± 0.2 g/mm2) in SHR. In contrast, ET promoted reduction in blood pressure and resting bradycardia in trained animals. ET corrected the VO2 peak reduction, change in proportion of muscle fiber types, soleus atrophy and dysfunction in SHR-T toward control levels. Interestingly, the muscle miRNA microarray analyzed by LC Science revealed a miRNAs profile involved in muscle remodeling (miRNAs-96, -205, -182, -140, -328a, -665, -1, -499, -208b and -99b) making it possible to identify target genes modified by hypertension and ET. Thus, targets involved in changing the fiber profile and protein synthesis by the IGF-I/ Akt /mTOR pathway were impaired in hypertension and corrected by ET. CONCLUSION: The results support the hypothesis that the structural and functional changes arising from the progression of hypertension may be regulated by a set of miRNAs and target genes; and ET participates in restoring the muscle mass and function.