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

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.

Long Noncoding RNA FTX Reduces Hypertrophy of Neonatal Mouse Cardiac Myocytes and Regulates the PTEN/PI3K/Akt Signaling Pathway by Sponging MicroRNA-22

“…In the present study, the expression of PI3K and Akt were increased by Ang II treatment, and this increased expression was reversed by lnc-FTX overexpression. Also, PTEN expression had the opposite effect to the expression of PI3K and Akt, which was consistent with the findings from a previously published study that showed that PTEN was a negative regulator of the PI3K/AKT signaling pathway [31]. The findings from the present study showed that lnc-FTX had a protective on hypertrophy of mouse cardiac myocytes induced by Ang II through inhibition of the PI3K/AKT signaling pathway by promoting the expression of PTEN and sponging miRNA-22.…”

Molecular Mechanisms of Cardiac Remodeling and Regeneration in Physical Exercise

“…Exercise-induced activation of PI3K/AKT/mTOR signaling and subsequent left ventricular physiological hypertrophy is not only mediated via disrupted miR-17 levels but also via other miR-clusters as shown in a rat model [63]: Ma et al found decreased miRNA-124 levels (targeting PI3K) and increased miRNAs-21, -144, and -145 (targeting PTEN and TSC-2), all leading to an induced activation of PI3K/Akt/mTOR signaling in cardiomyocytes. Furthermore swimming exercise and application of recombinant human growth hormone (r-hGH) in rats altered cardiac PI3K/Akt/mTOR signaling and miR-21 and miR-133 expression [96]. Reciprocal repression between miR-133 and calcineurin is involved in regulating cardiac hypertrophy [98].…”

MicroRNA-21-Enriched Exosomes as Epigenetic Regulators in Melanomagenesis and Melanoma Progression: The Impact of Western Lifestyle Factors

“…The GH-GHR axis induces chemoresistance in human MM by driving MITF-regulated and ABC-transporter-mediated drug clearance pathways [ 297 ]. Increased GH-JAK2-STAT3 signaling may thus explain the association between GH administration and MM ( Figure 2 ) [ 298 , 299 , 300 ]. Interestingly, the prepubertal somatotropic axis can be modified by milk consumption [ 301 , 302 ].…”