MiRNAs with Apoptosis Regulating Potential Are Differentially Expressed in Chronic Exercise-Induced Physiologically Hypertrophied Hearts

Abstract

Physiological cardiac hypertrophy is an adaptive mechanism, induced during chronic exercise. As it is reversible and not associated with cardiomyocyte death, it is considered as a natural tactic to prevent cardiac dysfunction and failure. Though, different studies revealed the importance of microRNAs (miRNAs) in pathological hypertrophy, their role during physiological hypertrophy is largely unexplored. Hence, this study is aimed at revealing the global expression profile of miRNAs during physiological cardiac hypertrophy. Chronic swimming protocol continuously for eight weeks resulted in induction of physiological hypertrophy in rats and histopathology revealed the absence of tissue damage, apoptosis or fibrosis. Subsequently, the total RNA was isolated and small RNA sequencing was executed. Analysis of small RNA reads revealed the differential expression of a large set of miRNAs during physiological hypertrophy. The expression profile of the significantly differentially expressed miRNAs was validated by qPCR. In silico prediction of target genes by miRanda, miRdB and TargetScan and subsequent qPCR analysis unraveled that miRNAs including miR-99b, miR-100, miR-19b, miR-10, miR-208a, miR-133, miR-191a, miR-22, miR-30e and miR-181a are targeting the genes that primarily regulate cell proliferation and cell death. Gene ontology and pathway mapping showed that the differentially expressed miRNAs and their target genes were mapped to apoptosis and cell death pathways principally via PI3K/Akt/mTOR and MAPK signaling. In summary, our data indicates that regulation of these miRNAs with apoptosis regulating potential can be one of the major key factors in determining pathological or physiological hypertrophy by controlling fibrosis, apoptosis and cell death mechanisms.

Aerobic exercise training promotes physiological cardiac remodeling involving a set of microRNAs

“…In contrast, exercise training decreased cardiac miRNA-124 expression associated with an increase in their target gene PI3K (p110-␣) involved in physiological hypertrophy. Recently, Ramasamy et al (80) also performed microarray miRNA in swimming training-induced cardiac hypertrophy, indicating that miRNA-30e, -133b, and -208 were significantly upregulated and miRNA-99b and -100 were significantly downregulated after real-time PCR confirmation in healthy rats. Target genes that regulate proliferation and cell death were showed, suggesting that PI3/Akt/mTOR, MAPK, and p53 signaling are involved in physiological cardiac growth.…”

Overexpression of miR-223 Tips the Balance of Pro- and Anti-hypertrophic Signaling Cascades toward Physiologic Cardiac Hypertrophy

“…miR-1, miR-133, miR199a/b, miR-21, miR-23, miR-26, miR-29, miR-9, miR-98, and miR-499) have been shown to exert either a positive or negative influence on pathological cardiac hypertrophy (4 -6). Whereas several studies have recently profiled microRNA expression signatures in rat physiological hypertrophic hearts induced by swimming or treadmill training, it still remains unknown how dys-regulated miRNAs contribute to physiological hypertrophy (7)(8)(9)(10).…”

The Role of MicroRNAs in the Cardiac Response to Exercise

“…Among these, 16 miRNAs, including miR-222, were independently validated as concordantly regulated in both models . In a recent study, Ramasamy et al (2015) sequenced RNA from the hearts of rats swum for 8 weeks and sedentary controls and found that .80% of the 201 detected miRNAs were differentially regulated. Among the 128 miRNAs with read counts of .1000, 95 miRNAs were altered .1.5-fold with an adjusted false discovery rate (FDR) ,0.1 (Ramasamy et al 2015).…”

“…In a recent study, Ramasamy et al (2015) sequenced RNA from the hearts of rats swum for 8 weeks and sedentary controls and found that .80% of the 201 detected miRNAs were differentially regulated. Among the 128 miRNAs with read counts of .1000, 95 miRNAs were altered .1.5-fold with an adjusted false discovery rate (FDR) ,0.1 (Ramasamy et al 2015). miRNAs changed .2.5-fold were miR208a, -19b, -133b, and -30e, which were all upregulated, and miR-99b, -100, -191a, -22, and -181a, which were all down-regulated.…”