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Estradiol Stimulates Mitochondrial Biogenesis and Adiponectin Expression in Skeletal Muscle

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Estradiol Stimulates Mitochondrial Biogenesis and Adiponectin Expression in Skeletal Muscle G CAPLLONCH-AMER and others Mitochondrial biogenesis 221:3 391–403 Research stimulation in WGM Estradiol stimulates mitochondrial biogenesis and adiponectin expression in skeletal muscle Gabriela Capllonch-Amer1, Miquel Sbert-Roig1, Bel M Galme´s-Pascual1, Ana M Proenza1,2, Isabel Llado´1,2, Magdalena Gianotti1,2 and Francisco J Garcı´a-Palmer1,2 1Grup Metabolisme Energe` tic i Nutricio´ , Departament de Biologia Fonamental i Cie` ncies de la Salut, Institut Correspondence Universitari d’Investigacio´ en Cie` ncies de la Salut (IUNICS), Universitat de les Illes Balears, Ctra. Valldemossa, should be addressed km 7,5. E-07122 Palma de Mallorca, Illes Balears, Spain to M Gianotti 2Centro de Investigacio´ n Biome´ dica en Red Fisiopatologı´a de la Obesidad y la Nutricio´ n (CIBERobn, CB06/03/0043), Email Instituto de Salud Carlos III, Madrid, Spain [email protected] Abstract Sexual dimorphism has been found in mitochondrial features of skeletal muscle, with female Key Words rats showing greater mitochondrial mass and function compared with males. Adiponectin is an " 17b-estradiol insulin-sensitizing adipokine whose expression has been related to mitochondrial function and " testosterone that is also expressed in skeletal muscle, where it exerts local metabolic effects. The aim of this " ovariectomy research was to elucidate the role of sex hormones in modulation of mitochondrial function, as " mitochondrial biogenesis well as its relationship with adiponectin production in rat skeletal muscle. An in vivo study with " mitochondrial dynamics ovariectomized Wistar rats receiving or not receiving 17b-estradiol (E2)(10mg/kg per 48 h for " skeletal muscle Journal of Endocrinology 4 weeks) was carried out, in parallel with an assay of cultured myotubes (L6E9) treated with " adiponectin E2 (10 nM), progesterone (Pg; 1 mM), or testosterone (1 mM). E2 upregulated the markers of " L6E9 mitochondrial biogenesis and dynamics, and also of mitochondrial function in skeletal muscle and L6E9. Although in vivo E2 supplementation only partially restored the decreased adiponectin expression levels induced by ovariectomy, these were enhanced by E2 and Pg treatment in cultured myotubes, whereas testosterone showed no effects. Adiponectin receptor 1 expression was increased by E2 treatment, both in vivo and in vitro, but testosterone decreased it. In conclusion, our results are in agreement with the sexual dimorphism previously reported in skeletal muscle mitochondrial function and indicate E2 to be its main effector, as it enhances mitochondrial function and diminishes oxidative stress. Moreover, our data support the idea of the existence of a link between mitochondrial function and adiponectin expression in skeletal muscle, which could be modulated by sex hormones. Journal of Endocrinology (2014) 221, 391–403 Introduction Sexual dimorphism in mitochondrial functionality has Guevara et al. 2009, Nadal-Casellas et al. 2011a, 2012, been described in many rat tissues such as liver, adipose Amengual-Cladera et al. 2012b). In all these tissues, female tissue, brain, and skeletal muscle (Colom et al. 2007a,b, rats present higher oxidative capacity than males, which Valle et al. 2007a,b, Go´mez-Pe´rez et al.2008, 2012, is associated with greater mitochondrial biogenesis and http://joe.endocrinology-journals.org Ñ 2014 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JOE-14-0008 Printed in Great Britain Downloaded from Bioscientifica.com at 09/26/2021 05:41:35AM via free access Research G CAPLLONCH-AMER and others Mitochondrial biogenesis 221:3 392 stimulation in WGM with morphological differences consisting of larger In skeletal muscle, adiponectin can be detected within mitochondria with greater cristae size and density. the myofibers and is involved in muscle contractile Oxidative stress status associated with physiopathological function, phenotype, and metabolism (Krause et al. situations such as caloric restriction, high-fat-diet feeding, 2008, Liu et al. 2009a). or aging, also shows sexual dimorphism, as female rats As skeletal muscle from female rats exhibits greater show lower oxidative damage than males, a fact that has mitochondrial mass, antioxidant protection, and been related to their higher antioxidant defences (Colom oxidative–phosphorylative capacities than that from et al. 2007b, Valle et al. 2007b, Go´mez-Pe´rez et al. 2008, males (Colom et al.2007a, Catala`-Niell et al.2008, Vin˜a et al. 2011, Amengual-Cladera et al. 2012b). In this Go´mez-Pe´rez et al. 2008), and E2 has been shown to play sexual dimorphism, 17b-estradiol (E2) would be a key a role in mitochondrial modulation in other tissues factor, as it plays a relevant role in mitochondrial (Mattson et al. 1997, Chen et al. 1999, Rodrı´guez-Cuenca modulation in tissues such as adipose tissue, liver, et al. 2007, Moreira et al. 2011, Nadal-Casellas et al. 2011b, and brain (Mattson et al. 1997, Chen et al.1999, Amengual-Cladera et al. 2012a,c), the aim of the present Rodrı´guez-Cuenca et al. 2007, Moreira et al. 2011, study was to elucidate the role of sex hormones in these Nadal-Casellas et al. 2011b, Amengual-Cladera et al. differences, as well as their relationship with adiponectin 2012a,c). As E2 is known to activate the expression of production in skeletal muscle. This was accomplished by specific proteins of the mitochondrial machinery and using a model of ovariectomized (OVX) rats to test the of genes controlling mitochondrial biogenesis and mito- effects of a decrease in ovarian hormone levels and of E2 chondrial DNA transcription (Klinge 2008, Mattingly replacement, combined with in vitro experiments with et al. 2008), this hormone ameliorates mitochondrial L6E9 myotubes, which were treated with E2, progesterone functionality, although its effects are tissue-specific (Pg), and testosterone. (Moreira et al. 2011). The role of E2 in sexual dimorphism of skeletal muscle mitochondrial function remains to be fully elucidated. Materials and methods E also plays a role in the regulation of body weight, 2 Animals and treatments and a loss of E2 is associated with the development of obesity (Chen et al. 2009), which is related to a decrease in Animal experiments were carried out in accordance with adiponectin levels in serum. Adiponectin is an insulin- general guidelines approved by our institutional ethics Journal of Endocrinology sensitizing hormone secreted mainly by white adipose committee and EU regulations (2010/63/UE). At 10 weeks tissue (WAT; Harwood 2012). Circulating levels of of age, Wistar rats (Charles River Laboratories, Barcelona, adiponectin show sexual dimorphism in both humans Spain) were distributed into three experimental groups: and rodents, with females presenting higher serum control female (nZ6), OVX (nZ6), and OVX supple- concentrations than males (Riestra et al. 2013). Adiponec- mented with E2 (OVXCE2, nZ6). Ovariectomy and sham tin expression in WAT is also greater in females than in surgery were performed at 5 weeks of age at Charles River males (Amengual-Cladera et al. 2012a,b,c), a fact that in Laboratories. Animals were housed in a controlled humans has been associated with sex hormone milieu environment (22 8C and 65G3% humidity) under a 12 h (Riestra et al. 2013, Wildman et al. 2013). Proper light:12 h darkness cycle with free access to water and mitochondrial function is essential for the production of pelleted standard diet (A04, Panlab, Barcelona, Spain). adiponectin in adipocytes (Koh et al. 2007), so impaired Every week, animals were weighed and food intake was mitochondrial function in WAT also has negative effects measured. For the OVXCE2 group, E2 (10 mg/kg per 48 h) on the insulin response in other tissues through a decrease was dissolved in corn oil and administered via s.c. in the expression and secretion of adiponectin (Wang et al. injection for the 4 weeks preceding killing, whereas the 2013). Furthermore, adiponectin plays an important OVX group was treated only with the vehicle. At 14 weeks role in the regulation of mitochondrial content and of age and after a period of 12 h fasting, rats were killed by function in other tissues such as skeletal muscle cervical decapitation. Trunk blood was collected and (Civitarese et al. 2006). Although it was originally white gastrocnemius muscle (WGM) was quickly removed, proposed that adiponectin was expressed and secreted frozen in liquid N2, and stored at K80 8C until analysis was only in adipose tissue, it has been shown to be also performed. The estrous cycle stage was regularly expressed in non-adipose tissues such as liver and muscle determined by measuring the vaginal wall impedance (Ding et al. 2007, Krause et al. 2008, Uribe et al. 2008). (Impeast, Cibertec, Madrid, Spain) and by microscopic http://joe.endocrinology-journals.org Ñ 2014 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JOE-14-0008 Printed in Great Britain Downloaded from Bioscientifica.com at 09/26/2021 05:41:35AM via free access Research G CAPLLONCH-AMER and others Mitochondrial biogenesis 221:3 393 stimulation in WGM evaluation of the vaginal smears. All the control animals Western blot analysis were in diestrus phase at the time they were killed. Briefly, 30 mg protein from the homogenates were frac- tioned by using SDS–PAGE (10–12% acrylamide) and Serum and blood parameters electrotransferred onto a nitrocellulose membrane. The membranes were blocked with blocking solution (5% Blood was allowed to clot for 20 min and then it was nonfat powdered milk in PBS, pH 7.5, containing
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