The molecular mechanisms of anabolic androgen actions in skeletal muscle

我们正在研究男性荷尔蒙在控制肌肉功能方面的作用。肌肉萎缩发生在各种疾病中，包括癌症、烧伤和创伤，在正常衰老过程中也会发生。使用雄激素治疗有助于防止肌肉萎缩，并导致肌肉大小增加，尽管目前的治疗方法也有副作用。关于雄激素如何防止消瘦和促进肌肉生长，人们知之甚少。因此，我们建议研究男性荷尔蒙在肌肉中的作用。我们将研究小鼠肌肉细胞在培养中的生长情况，并测量它们在雄激素处理时的生长速度。所有细胞都含有控制其生长和复制的某些因素，我们将测试雄激素是否激活这些因素以促进生长。我们还将研究雄激素对小鼠肌肉的影响，以调查仅在真实肌肉中发生的复杂影响。我们将给雄性老鼠绝育，这会导致肌肉萎缩。然后，绝育小鼠将接受雄激素或安慰剂治疗，我们将比较雄激素治疗和安慰剂对肌肉生长的影响。我们将测量接受治疗和服用安慰剂的小鼠的肌肉力量、大小和肌细胞数量。我们还将研究雄激素的作用是否需要一种特定的蛋白质，雄激素受体，它在细胞中起着锁钥机制的作用，允许它们对雄激素做出反应。我们将制造一种只在肌肉细胞中使用雄激素受体的非功能版本的小鼠。这将决定雄激素对肌肉生长的影响是通过对肌肉的直接作用发生的，还是通过对身体其他组织的作用间接发生的。这些信息最终将使我们能够为肌肉萎缩设计更有针对性的雄激素疗法，这些疗法只对肌肉起作用。

We are studying the role of male sex hormones, androgens, in controlling muscle function. Muscle wasting occurs in a variety of disorders, including cancer, burns and trauma, and also during normal ageing. Treatment with androgens helps prevent muscle wasting, and causes increased muscle size, although current therapies can also have side effects. Little is known about how androgens prevent wasting and promote muscle growth. Therefore, we propose to study the actions of male sex hormones in muscle. We will study the growth of mouse muscle cells in culture, and measure their rate of growth when treated with androgens. All cells contain certain factors that control their growth and replication, and we will test whether androgens activate these factors to increase growth. We will also study the effect of androgens on muscle in mice, to investigate complex effects that only occur in real muscle. We will neuter male mice, which causes muscle wasting. Neutered mice will then be treated with androgens or placebo, and we will compare the muscle growth effect of androgen treatment versus placebo. We will measure muscle strength, size, and the number of muscle cells in treated and placebo mice. We will also see if the effects of androgen require a particular protein, the androgen receptor, which acts as a lock-key mechanism in cells, to allow them to respond to androgens. We will make a strain of mouse with a non-functional version of the androgen receptor only in muscle cells. This will determine if the muscle growth effects of androgens occur through a direct action on muscle, or indirectly through acting on other tissues in the body. This information will ultimately allow us to design more targeted androgen therapies for muscle wasting, that act only on muscle.