Testosterone increases GLUT4‐dependent glucose uptake in cardiomyocytes

Abstract

Testosterone exerts important effects in the heart. Cardiomyocytes are target cells for androgens, and testosterone induces rapid effects via Ca(2+) release and protein kinase activation and long-term effects via cardiomyocyte differentiation and hypertrophy. Furthermore, it stimulates metabolic effects such as increasing glucose uptake in different tissues. Cardiomyocytes preferentially consume fatty acids for ATP production, but under particular circumstances, glucose uptake is increased to optimize energy production. We studied the effects of testosterone on glucose uptake in cardiomyocytes. We found that testosterone increased uptake of the fluorescent glucose analog 2-(N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl)amino)-2-deoxyglucose and [(3) H]2-deoxyglucose, which was blocked by the glucose transporter 4 (GLUT4) inhibitor indinavir. Testosterone stimulation in the presence of cyproterone or albumin-bound testosterone-induced glucose uptake, which suggests an effect that is independent of the intracellular androgen receptor. To determine the degree of GLUT4 cell surface exposure, cardiomyocytes were transfected with the plasmid GLUT4myc-eGFP. Subsequently, testosterone increased GLUT4myc-GFP exposure at the plasma membrane. Inhibition of Akt by the Akt-inhibitor-VIII had no effect. However, inhibition of Ca(2+) /calmodulin protein kinase (CaMKII) (KN-93 and autocamtide-2 related inhibitory peptide II) and AMP-activated protein kinase (AMPK) (compound C and siRNA for AMPK) prevented glucose uptake induced by testosterone. Moreover, GLUT4myc-eGFP exposure at the cell surface caused by testosterone was also abolished after CaMKII and AMPK inhibition. These results suggest that testosterone increases GLUT4-dependent glucose uptake, which is mediated by CaMKII and AMPK in cultured cardiomyocytes. Glucose uptake could represent a mechanism by which testosterone increases energy production and protein synthesis in cardiomyocytes.

Testosterone stimulates glucose uptake and GLUT4 translocation through LKB1/AMPK signaling in 3T3-L1 adipocytes

“…Recently, Wilson et al [19] reported that testosterone (100 nM) stimulates glucose uptake through GLUT4 and activates the CaMKII/AMPK signaling pathway in cultured cardiomyocytes. The results of Western blot analysis with anti-phospho-CaMKI antibodies and a time-course examination of the CaMKII and AMPK phosphorylation in this study suggest that testosterone-BSA stimulates GLUT4-dependent glucose uptake through activation of the Ca 2?…”

“…Clinical and experimental studies have shown that low serum testosterone concentrations are linked to metabolic disorders, including metabolic syndrome, type 2 diabetes, and hepatic steatosis [11][12][13][14][15][16][17]. In addition, testosterone has been reported to increase GLUT4-dependent glucose uptake in skeletal muscle cells and cardiomyocytes [18,19]. However, studies on glucose uptake occurring in response to testosterone stimulation in adipocytes are currently not available.…”

Prenatal programming: adverse cardiac programming by gestational testosterone excess

“…T has been found to increase cardiomyocyte glucose uptake by augmenting GLUT4 translocation56 and although an increase in GLUT 4 protein expression was not seen in the left ventricle under basal condition, the increase in expression of insulin signaling proteins including IRS-1, PI3K and AKT is suggestive of increase in glucose metabolism within the left ventricle. Free fatty acids are the primary fuel for energy production in cardiac tissue but during fetal life and during times of stress, the heart does revert to glucose as its primary source of fuel57.…”

Fibronectin type III domain containing 5 expression in skeletal muscle in chronic heart failure—relevance of inflammatory cytokines

“…Recombinant TNF-α (10 ng/mL), IL-1ß (50 ng/mL), IFN-γ (10 ng/mL), or Ang-II (100 ng/mL) were added to the cell culture medium, and cells were incubated for 24 h before RNA expression of FNDC5 or PGC-1α was analysed in the myotubes by reverse transcription (RT)-PCR. The effects of PD98059 (50 µmol/L; Calbiochem, La Jolla, CA, USA), a specific inhibitor of p42/44 mitogen-activated protein kinase (MAPK),18 SB203580 (10 µmol/L; Calbiochem, La Jolla, Ca, USA), a specific p38-MAPK inhibitor,19 chelerythrine (2 µmol/L; Sigma, Taufkirchen, Germany), a specific protein kinase C (PKC) inhibitor,20 SP600125 (20 µmol/L; Sigma, Taufkirchen, Germany), a specific c-Jun N-terminal kinase inhibitor,21 Akt inhibitor VIII (20 µmol/L; Sigma Taufkirchen, Germany),22 and nifuroxazide (10 µmol/L; Santa Cruz, Heidelberg, Germany), a specific signal transducer and activator of transcription 3 (STAT-3) inihibitor23 on FNDC5 expression, were tested by pre-incubating cells for 2 h before the addition of inflammatory cytokines.…”