Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, 3084, Australia.
Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, 3084, Australia.
J Steroid Biochem Mol Biol. 2019 May;189:187-194. doi: 10.1016/j.jsbmb.2019.02.018. Epub 2019 Mar 8.
We have previously shown that expression of the androgen receptor (AR) in neurons within the brain positively regulates hind-limb muscle mass and physical activity in male mice. To further investigate the region of the brain responsible for mediating these effects of testosterone and to determine whether they are only important for muscle mass accrual during development or whether they are also important for the maintenance of muscle mass in the adult, we deleted the AR specifically in the hypothalamus of adult male mice (Hyp-ARKOs). Hyp-ARKO mice were generated by bilateral stereotaxic microinjection of an adeno-associated virus (AAV) expressing GFP and iCre recombinase under the control of the e-synapsin promoter into the hypothalamus of 10-week-old exon 3-AR floxed male mice. AR mRNA was deleted by 45% in the hypothalamus of Hyp-ARKOs at 5 weeks post-AAV-eSyn-iCre injection. This led to an increase in the mass of the androgen-dependent organs, seminal vesicles and kidneys, by 30% (P < 0.01) and 10% (P < 0.05) respectively, and an increase in serum luteinizing hormone (LH) by 2 fold (P < 0.05). Whilst the mean value for serum testosterone was higher in the Hyp-ARKOs, this did not reach statistical significance. Despite a phenotype consistent with increased androgen bioactivity in Hyp-ARKOs, which would be expected to increase muscle mass, the mass of the hind-limb muscles, gastrocnemius (Gast) (P = 0.001), extensor digitorum longus (EDL) (P < 0.001) and soleus (Sol) (P < 0.01) were paradoxically decreased by 12-19% compared to controls. Voluntary physical activity was reduced by 65% (P < 0.05) in Hyp-ARKO male mice and was associated with a reduction in gene expression of Drd1a and Maob (P ≤ 0.05) in the hypothalamus, suggesting involvement of the brain dopaminergic system. These data provide compelling evidence that androgen signalling via the AR in the hypothalamus acts to positively regulate the maintenance of hind-limb muscle mass and voluntary activity in adult male mice, independent of AR signalling in peripheral tissues.
我们之前的研究表明，脑内神经元中雄激素受体 (AR) 的表达可正向调节雄性小鼠后肢肌肉量和体力活动。为了进一步研究负责介导睾酮这些作用的脑区，并确定它们是否仅对发育过程中肌肉量的积累很重要，还是对成年后肌肉量的维持也很重要，我们在成年雄性小鼠的下丘脑特异性删除了 AR（Hyp-ARKO）。Hyp-ARKO 小鼠通过双侧立体定位微注射携带 GFP 和 iCre 重组酶的腺相关病毒 (AAV) 产生，该病毒受 e-synapsin 启动子控制，注入 10 周龄 exon3-AR floxed 雄性小鼠的下丘脑。AAV-eSyn-iCre 注射后 5 周，Hyp-ARKO 小鼠的下丘脑 AR mRNA 被删除了 45%。这导致雄激素依赖性器官精囊和肾脏的质量分别增加了 30%（P<0.01）和 10%（P<0.05），血清黄体生成素 (LH) 增加了 2 倍（P<0.05）。虽然 Hyp-ARKO 中的血清睾酮平均值较高，但未达到统计学意义。尽管 Hyp-ARKO 中存在与雄激素生物活性增加一致的表型，这预计会增加肌肉量，但后肢肌肉、比目鱼肌 (Gast)（P=0.001）、趾长伸肌 (EDL)（P<0.001）和比目鱼肌 (Sol)（P<0.01）的质量却出人意料地减少了 12-19%。Hyp-ARKO 雄性小鼠的自愿体力活动减少了 65%（P<0.05），并且与下丘脑 Drd1a 和 Maob 的基因表达减少有关（P≤0.05），提示涉及大脑多巴胺能系统。这些数据提供了令人信服的证据，表明雄激素通过 AR 在下丘脑的信号转导正向调节成年雄性小鼠后肢肌肉量和自愿活动的维持，而与外周组织中的 AR 信号转导无关。
