Testosterone activates glucose metabolism through AMPK and androgen signaling in cardiomyocyte hypertrophy

Abstract

Background Testosterone regulates nutrient and energy balance to maintain protein synthesis and metabolism in cardiomyocytes, but supraphysiological concentrations induce cardiac hypertrophy. Previously, we determined that testosterone increased glucose uptake—via AMP-activated protein kinase (AMPK)—after acute treatment in cardiomyocytes. However, whether elevated glucose uptake is involved in long-term changes of glucose metabolism or is required during cardiomyocyte growth remained unknown. In this study, we hypothesized that glucose uptake and glycolysis increase in testosterone-treated cardiomyocytes through AMPK and androgen receptor (AR). Methods Cultured cardiomyocytes were stimulated with 100 nM testosterone for 24 h, and hypertrophy was verified by increased cell size and mRNA levels of β-myosin heavy chain (β-mhc). Glucose uptake was assessed by 2-NBDG. Glycolysis and glycolytic capacity were determined by measuring extracellular acidification rate (ECAR). Results Testosterone induced cardiomyocyte hypertrophy that was accompanied by increased glucose uptake, glycolysis enhancement and upregulated mRNA expression of hexokinase 2. In addition, testosterone increased AMPK phosphorylation (Thr172), while inhibition of both AMPK and AR blocked glycolysis and cardiomyocyte hypertrophy induced by testosterone. Moreover, testosterone supplementation in adult male rats by 5 weeks induced cardiac hypertrophy and upregulated β-mhc, Hk2 and Pfk2 mRNA levels. Conclusion These results indicate that testosterone stimulates glucose metabolism by activation of AMPK and AR signaling which are critical to induce cardiomyocyte hypertrophy.

Analysis of the Serum Peptidomics Profile for Cats With Sarcomeric Gene Mutation and Hypertrophic Cardiomyopathy

“…Additional studies may involve understanding the risk factors for cardiovascular disease. Many studies have investigated the pathway that plays critical roles in mediating cardiac hypertrophy ( 9 – 12 ). The mechanisms for the effect of testosterone on muscle hypertrophy are not entirely understood.…”

Nandrolone supplementation promotes AMPK activation and divergent18[FDG] PET brain connectivity in adult and aged mice

“…Here we showed that the use of nandrolone induces an increase in AMPK, a key metabolic regulator in hypothalamic tissue. This increase in AMPK activation (pAMPK Thr172 ) following the acute use of steroid hormones has been described in other tissues, such as human cardiomyocytes 27 , skeletal muscle 28 , and the hypothalamic arcuate nucleus of guinea pigs 29 . We currently expand this concept by demonstrating that this effect is not restricted only to arcuate nucleus, but may be related to whole hypothalamus, and that it is sustained for at least 14 days, in both adult and aged mice.…”

“…Here, we demonstrated that ND supplementation induces increased AMPK phosphorylation, a key metabolic regulator in the hypothalamic brain area. This increase in AMPK activation (pAMPK Thr172 ) following the acute use of steroid hormones has been described in other tissues, such as human cardiomyocytes [39], skeletal muscle [40], and the hypothalamic arcuate nucleus of guinea pigs [41]. Herein, we expanded this concept by demonstrating that AMPK activation is not restricted to the arcuate nucleus subregion but may be part of the entire hypothalamic signaling strategy to regulate energy homeostasis.…”

“…The copyright holder for this this version posted October 19, 2021. ; https://doi.org/10.1101/2021.10.19.465014 doi: bioRxiv preprint tissues, such as human cardiomyocytes 27 , skeletal muscle 28 , and the hypothalamic arcuate nucleus of guinea pigs 29 . We currently expand this concept by demonstrating that this effect is not restricted only to arcuate nucleus, but may be related to whole hypothalamus, and that it is sustained for at least 14 days, in both adult and aged mice.…”

The effects of low‐intensity exercise on cardiac glycogenesis and glycolysis in male and ovariectomized female rats on a fructose‐rich diet

“…In contrast, in males, both a fructose diet and exercise can downregulate and upregulate, respectively, circulating testosterone concentration (Matos et al, 2019;Sakamuri et al, 2016). On the other hand, testosterone is known to enhance glucose transport via membrane GLUT4, stimulate the expression of glycolysis enzyme PFK-2 (Troncoso et al, 2021) and increase phosphorylation of GSK-3 in the cardiomyocytes (Duran et al, 2016). A possible positive effect of exercise on testosterone levels may, for example, be associated with an increased level of GSK-3β phosphorylation in EF versus SF male rats.…”