Testosterone and DHEA activate the glucose metabolism-related signaling pathway in skeletal muscle

Abstract

Sato K, Iemitsu M, Aizawa K, Ajisaka R. Testosterone and DHEA activate the glucose metabolism-related signaling pathway in skeletal muscle. Am J Physiol Endocrinol Metab 294: E961-E968, 2008. First published March 18, 2008 doi:10.1152/ajpendo.00678.2007.-Circulating dehydroepiandrosterone (DHEA) is converted to testosterone or estrogen in the target tissues. Recently, we demonstrated that skeletal muscles are capable of locally synthesizing circulating DHEA to testosterone and estrogen. Furthermore, testosterone is converted to 5␣-dihydrotestosterone (DHT) by 5␣-reductase and exerts biophysiological actions through binding to androgen receptors. However, it remains unclear whether skeletal muscle can synthesize DHT from testosterone and/or DHEA and whether these hormones affect glucose metabolism-related signaling pathway in skeletal muscles. We hypothesized that locally synthesized DHT from testosterone and/or DHEA activates glucose transporter-4 (GLUT-4)-regulating pathway in skeletal muscles. The aim of the present study was to clarify whether DHT is synthesized from testosterone and/or DHEA in cultured skeletal muscle cells and whether these hormones affect the GLUT-4-related signaling pathway in skeletal muscles. In the present study, the expression of 5␣-reductase mRNA was detected in rat cultured skeletal muscle cells, and the addition of testosterone or DHEA increased intramuscular DHT concentrations. Addition of testosterone or DHEA increased GLUT-4 protein expression and its translocation. Furthermore, Akt and protein kinase C-/ (PKC-/) phosphorylations, which are critical in GLUT-4-regulated signaling pathways, were enhanced by testosterone or DHEA addition. Testosterone-and DHEA-induced increases in both GLUT-4 expression and Akt and PKC-/ phosphorylations were blocked by a DHT inhibitor. Finally, the activities of phosphofructokinase and hexokinase, main glycolytic enzymes, were enhanced by testosterone or DHEA addition. These findings suggest that skeletal muscle is capable of synthesizing DHT from testosterone, and that DHT activates the glucose metabolism-related signaling pathway in skeletal muscle cells. 5␣-dihydrotestosterone; dehydroepiandrosterone; glucose transporter-4; Akt; protein kinase C-/ SEX STEROID HORMONES ARE MAINLY produced and secreted by the ovary, testis, and adrenal cortex and affect diverse physiological processes of target organs or tissues, such as reproductive organs, bones, liver, heart, vasculature, brain, and skeletal muscles (22). Synthesis of testosterone is regulated by P-450 side-chain cleavage, 17␣-hydroxylase cytochrome P-450, 17␤-hydroxysteroid dehydrogenase (HSD), and 3␤-HSD enzymes. Dehydroepiandrosterone (DHEA) is a presubstance of sex steroid hormones, and DHEA is converted to testosterone by 17␤-HSD and 3␤-HSD enzymes (23). Recently, our laboratory found that 3␤-HSD, 17␤-HSD, and aromatase cytochrome P-450 existed in cultured skeletal muscle and steroid hormones, including testosterone, and were locally synthesized from DHEA (1). In a skeletal muscle specim...

The Exercise-Induced Improvement in hyperglycemia is Mediated by DHT Produced in the Skeletal Muscle of Zucker Diabetic Fatty Rats

“…We demonstrated that acute and chronic exercise significantly increases muscular DHEA and DHT levels, and upregulates enzymes involved in steroidogenesis in normal and obese rats [10,11,13,14]. Furthermore, DHEA and DHT activate Akt and PKCζ/λ-GLUT-4 pathways in skeletal muscle [8]. Exercise-induced alleviation of insulin resistance was correlated with increased DHEA and DHT levels and activated Akt and PKCζ/λ-GLUT-4 pathways in the skeletal muscle of obese rats [11,12].…”

“…Samples (50 µg protein) were denatured at 96°C for 7 min in Laemmli buffer. Western blot analyses were performed essentially as previously described (Sato et al [8]). Briefly, samples were separated using 10% SDS-polyacrylamide gels and transferred to polyvinylidene difluoride membranes (PVDF; Millipore Corp., Billerica, MA).…”

“…DHEA is converted to testosterone by 3β-hydroxysteroid dehydrogenase (HSD) and 17β-HSD, and is converted to 5α-dehydrotestosterone (DHT) by 5α-reductase in peripheral tissues such as the ovary, testis, brain and bone [6]. Recently, we demonstrated that DHEA is metabolized to testosterone and DHT in cultured skeletal muscle, suggesting that skeletal muscle is capable of locally synthesizing sex steroid hormones [7,8]. Blood DHEA and DHEA-S levels in patients with type 2 diabetes are reduced [9].…”

Dihydrotestosterone is elevated following sprint exercise in healthy young men

“…These hormonal responses have been implicated both in the execution of acute workout performance and in the accrual of adaptive training gains (9). A variety of mechanisms have been proposed to support these actions, including the activation of cell signaling pathways promoting the mobilization of energy reserves via glutamine transporter 4 (GLUT4) (33) and the accretion of protein for skeletal muscle hypertrophy (15) via mTor (38), modulation of the excitability of neuromotor units (6), and more complex influences on behavioral motivation (4) and cognition (3). However, the precise nature of the interaction between hormonal response and functional outcome in a given exercise setting remains poorly understood.…”

Species specificity of an adrenal androgen-mediated kill-switch triggered by p53 inactivation

“…In cells with inactivated p53, loss of p53-mediated NFκB inhibition will result in upregulation of steroid sulfatase, increasing intracellular DHEA concentrations which will accelerate the feed forward uncompetitive inhibition of G6PD. Intracellular DHEA potentiates this process still further by inducing GLUT4 and HK activity, 32 raising G6P levels, and by enabling G6P to accumulate by inhibiting Glucose-6-phosphatase. 33 This would represent a sort of dead man switch for p53 in which its inactivation activates its back-up, DHEA.…”