Alteration in cardiac PI3K/Akt/mTOR and ERK signaling pathways with the use of growth hormone and swimming, and the roles of miR21 and miR133

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Abstract
Athletes misuse recombinant human growth hormone (r‑hGH) to enhance their performance. Although r‑hGH is known to increase cardiac hypertrophy, the underlying molecular mechanism remains unclear. The aim of the present study was to investigate the role of r‑hGH in cardiac intracellular signaling pathways and of miR‑21 and miR‑133 expression in rat hearts during exercise. A total of 36 adult male Sprague‑Dawley rats were divided into sedentary control (SC, n=9), swimming exercise (SE, n=8), r‑hGH (GH, n=10) and swimming exercise plus r‑hGH (SE‑GH, n=9) groups. The exercise groups completed a 1‑h swimming exercise 5 times a week for 8 weeks. Subcutaneous r‑hGH was administered as 0.3 mg/kg/day. Phosphoinositide‑3‑kinase (PI3K), serine/threonine protein kinase 1 (AKT1), extracellular signal‑regulated kinase (ERK), microRNA (miR)‑21 and miR‑133 expression was evaluated in ventricular muscle by real‑time quantitative polymerase chain reaction. Protein expression of PI3K, AKT1, ERK and mechanistic target of rapamycin (mTOR) was also assessed by immunohistochemistry. Statistical differences were analyzed by two‑way ANOVA. PI3K and AKT1 expression and the gene and protein levels was notably increased in the SE‑GH group compared with in SC ventricular tissues (P<0.05). mTOR protein expression was higher in the GH, SE and SE‑GH groups compared with in the SC group (P<0.05, <0.05 and <0.001, respectively). ERK gene/protein expression was similar across all groups. miR‑21 and miR‑133 levels in ventricular muscle were higher in the SE and GH groups than those in the SC group. In summary, growth hormone application coupled with swimming exercise appeared to affect the PI3K/AKT/mTOR signaling pathway in the left ventricular tissue of rats; however, ERK signaling pathway appeared inactive in physiological left ventricular hypertrophy caused by swimming and GH administration over 8 weeks. Furthermore, GH treatment resulted in increased miR‑21 and miR‑133 expression. Future study by our group will aim to assess the effects of higher dose GH treatment.

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