The molecular mechanisms of anabolic androgen actions in skeletal muscle

我们正在研究男性性激素，雄激素在控制肌肉功能中的作用。肌肉萎缩发生在各种疾病中，包括癌症、烧伤和创伤，也发生在正常衰老过程中。用雄激素治疗有助于防止肌肉萎缩，并导致肌肉尺寸增加，尽管目前的治疗也有副作用。人们对雄激素如何防止肌肉萎缩和促进肌肉生长知之甚少。因此，我们建议研究男性性激素在肌肉中的作用。我们将研究培养小鼠肌肉细胞的生长情况，并测量它们在雄激素作用下的生长速度。所有细胞都含有控制其生长和复制的某些因子，我们将测试雄激素是否激活这些因子以促进生长。我们还将研究雄激素对小鼠肌肉的影响，以研究仅发生在真实肌肉中的复杂效应。我们将给雄性老鼠阉割，这会导致肌肉萎缩。然后用雄激素或安慰剂治疗绝育小鼠，我们将比较雄激素治疗和安慰剂治疗对肌肉生长的影响。我们将测量治疗小鼠和安慰剂小鼠的肌肉力量、大小和肌肉细胞数量。我们还将看到雄激素的作用是否需要一种特殊的蛋白质，雄激素受体，它在细胞中起着锁锁机制的作用，允许它们对雄激素做出反应。我们将制造一种仅在肌肉细胞中具有无功能雄激素受体的小鼠。这将决定雄激素对肌肉生长的影响是通过直接作用于肌肉，还是间接作用于身体其他组织。这一信息最终将使我们能够设计出更有针对性的雄激素疗法来治疗肌肉萎缩，这种疗法只作用于肌肉。

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.