These results suggest a crosstalk between pathways involving fast intracellular signaling and the AR to explain testosterone-induced skeletal muscle hypertrophy.

No abstract

Sarcopenia, the age-related loss of skeletal muscle mass and function, is becoming more prevalent as the lifespan continues to increase in most populations. As sarcopenia is highly disabling, being associated with increased risk of dependence, falls, fractures, weakness, disability, and death, development of approaches to its prevention and treatment are required. Androgens are the main physiologic anabolic steroid hormones and normal testosterone levels are necessary for a range of developmental and biological processes, including maintenance of muscle mass. Testosterone concentrations decline as age increase, suggesting that low plasma testosterone levels can cause or accelerate muscle- and age-related diseases, as sarcopenia. Currently, there is increasing interest on the anabolic properties of testosterone for therapeutic use in muscle diseases including sarcopenia. However, the pathophysiological mechanisms underlying this muscle syndrome and its relationship with plasma level of androgens are not completely understood. This review discusses the recent findings regarding sarcopenia, the intrinsic, and extrinsic mechanisms involved in the onset and progression of this disease and the treatment approaches that have been developed based on testosterone deficiency and their implications.

Seven healthy young men were submitted twice to a hypoxia tolerance test at a simulated altitude (3000 m). Their first acute exposure was in a hypobaric chamber; and the second, in a hypoxic tent. Cardiorespiratory parameters and heart rate variability measurements were obtained under each hypoxic condition. A significant decrease of 6% to 8% compared to normal oxygen conditions was observed in arterial oxygen saturation (SpO 2 ) in both hypoxic conditions at rest; whereas exercise led to decreases of 10% in SpO 2 despite an increase of 27% in respiratory minute volume. The low frequency (LF) and high frequency (HF) components of heart rate variability significantly changed from normoxia (LF: 37.1, HF: 62.9, LF/HF: 1.27) to hypobaric hypoxia (HH) (LF: 49.1, HF: 50.6, LF/HF: 1.96). However, these changes were not observed under normobaric hypoxia. Thus, heart rate variability behaved differently in the two hypoxic conditions, supporting the hypothesis that normobaric hypoxia and hypobaric hypoxia are not equal stimuli to the cardiovascular and respiratory systems. A correlation was found between sympathetic and vagal modulations in normoxia and SpO 2 at exercise under hypobaric hypoxia (HH). Individuals with higher sympathetic modulation (LF%) in normoxia had higher SpO 2 at exercise under HH (r = 0.808, P < 0.05) and individuals with higher vagal modulation (HF%) in normoxia showed a trend to lower SpO 2 in exercise under HH (r = −0.636, P = 0.125). This opens up the possibility of using this correlation as a tool for predicting the individual capacity to altitude acclimatization. © 2011 Consell Català de l'Esport. Generalitat de Catalunya. Published by Elsevier España, S.L. All rights reserved. * Corresponding author. E-mail address: gviscor@ub.edu (G. Viscor). PALABRAS CLAVEVariabilidad de la frecuencia cardiaca; Prueba de tolerancia a hipoxia; Tienda hipóxica; Cámara hipobárica; Saturación arterial de oxígeno Parámetros cardiorrespiratorios durante ejercicio submáximo en hipoxia aguda hipobárica y normobáricaResumen Siete jóvenes sanos y en buena condición física realizaron dos pruebas de tolerancia a hipoxia a una altitud simulada de 3.000 m. La primera fue en cámara hipobárica, mientras que la segunda se efectuó en una tienda hipóxica. Se registraron varios parámetros cardiorrespiratorios y la variabilidad de la frecuencia cardiaca. En comparación con las condiciones de normoxia, se observó un decremento significativo del 6% al 8% en la saturación de oxígeno arterial (SpO 2 ) en reposo en ambas condiciones de hipoxia. El ejercicio desencadenó descensos de un 10% en SpO 2 pese a un incremento del 27% del volumen minuto ventilatorio. Tanto los componentes de baja (LF) como alta frecuencia (HF) de la variabilidad del ritmo cardiaco cambiaron significativamente en hipoxia hipobárica (LF: 49,1, HF: 50,6, LF/HF: 1,96) respecto a normoxia (LF: 37,1, HF: 62,9, LF/HF: 1,27). Estos cambios no se apreciaron en condiciones de hipoxia normobárica, lo cual apoya la hipótesis de que la hipoxia hipobárica y norm...

Testosterone induces cardiac hypertrophy through a mechanism that involves a concerted crosstalk between cytosolic and nuclear signaling pathways. Nuclear factor of activated T-cells (NFAT) is associated with the promotion of cardiac hypertrophy, glycogen synthase kinase-3β (GSK-3β) is considered to function as a negative regulator, mainly by modulating NFAT activity. However, the role played by calcineurin-NFAT and GSK-3β signaling in testosterone-induced cardiac hypertrophy has remained unknown. Here, we determined that testosterone stimulates cardiac myocyte hypertrophy through NFAT activation and GSK-3β inhibition. Testosterone increased the activity of NFAT-luciferase (NFAT-Luc) in a time- and dose-dependent manner, with the activity peaking after 24 h of stimulation with 100 nM testosterone. NFAT-Luc activity induced by testosterone was blocked by the calcineurin inhibitors FK506 and cyclosporine A and by 11R-VIVIT, a specific peptide inhibitor of NFAT. Conversely, testosterone inhibited GSK-3β activity as determined by increased GSK-3β phosphorylation at Ser9 and β-catenin protein accumulation, and also by reduction in β-catenin phosphorylation at residues Ser33, Ser37, and Thr41. GSK-3β inhibition with 1-azakenpaullone or a GSK-3β-targeting siRNA increased NFAT-Luc activity, whereas overexpression of a constitutively active GSK-3β mutant (GSK-3βS9A) inhibited NFAT-Luc activation mediated by testosterone. Testosterone-induced cardiac myocyte hypertrophy was established by increased cardiac myocyte size and [3H]-leucine incorporation (as a measurement of cellular protein synthesis). Calcineurin-NFAT inhibition abolished and GSK-3β inhibition promoted the hypertrophy stimulated by testosterone. GSK-3β activation by GSK-3βS9A blocked the increase of hypertrophic markers induced by testosterone. Moreover, inhibition of intracellular androgen receptor prevented testosterone-induced NFAT-Luc activation. Collectively, these results suggest that cardiac myocyte hypertrophy induced by testosterone involves a cooperative mechanism that links androgen signaling with the recruitment of NFAT through calcineurin activation and GSK-3β inhibition.

Among multiple mechanisms, low-grade inflammation is critical for the development of insulin resistance as a feature of type 2 diabetes. The nucleotide-binding oligomerization domain-like receptor family (NOD-like) pyrin domain containing 3 (NLRP3) inflammasome has been linked to the development of insulin resistance in various tissues; however, its role in the development of insulin resistance in the skeletal muscle has not been explored in depth. Currently, there is limited evidence that supports the pathological role of NLRP3 inflammasome activation in glucose handling in the skeletal muscle of obese individuals. Here, we have centered our focus on insulin signaling in skeletal muscle, which is the main site of postprandial glucose disposal in humans. We discuss the current evidence showing that the NLRP3 inflammasome disturbs glucose homeostasis. We also review how NLRP3-associated interleukin and its gasdermin D-mediated efflux could affect insulin-dependent intracellular pathways. Finally, we address pharmacological NLRP3 inhibitors that may have a therapeutical use in obesity-related metabolic alterations.

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.

No abstract