Impaired skeletal muscle development and function in male, but not female, genomic androgen receptor knockout mice
Impaired skeletal muscle development and function in male, but not female, genomic androgen receptor knockout mice
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DOI：
10.1096/fj.08-105726
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发表时间：
2008-08-01
期刊：
影响因子：
4.8
通讯作者：
Zajac, Jeffrey D.
中科院分区：
文献类型：
--
作者：
MacLean, Helen E.;Chiu, W. S. Maria;Zajac, Jeffrey D.
为了确定肌肉中合成代谢雄激素作用的机制，我们产生了雄性和雌性基因组雄激素受体（AR）敲除（ARKO）小鼠，并表征了肌肉质量、收缩功能和基因表达。ARKO雄性的肌肉质量降低，但ARKO雌性的肌肉质量正常。肛提肌在正常女性中无法发育，在ARKO男性中也不存在。力量生产减少从快收缩ARKO男性肌肉，和慢收缩肌肉增加抗疲劳性。微阵列分析显示编码慢肌收缩蛋白的基因上调。实时PCR证实，编码多胺生物合成酶，鸟氨酸脱羧酶（Odc 1）和S-腺苷甲硫氨酸脱羧酶（Amd 1）的基因的表达在ARKO肌肉中减少，表明雄激素通过调节多胺生物合成起作用。成肌细胞从增殖到终末分化的调节因子的表达改变表明雄激素也通过维持成肌细胞处于增殖状态和延迟分化（增加Cdkn 1c和Igf 2，减少Itg 1bp 3）来促进肌肉生长。在雄激素戒断依赖性肌肉萎缩期间，在去势雄性小鼠中观察到类似的基因表达模式。总之，雄激素是不需要的峰值肌肉质量的女性。在男性中，雄激素通过AR来调节控制肌肉质量、力量和抗疲劳性的多个基因通路。
To identify mechanisms of anabolic androgen action in muscle, we generated male and female genomic androgen receptor (AR) knockout (ARKO) mice, and characterized muscle mass, contractile function, and gene expression. Muscle mass is decreased in ARKO males, but normal in ARKO females. The levator ani muscle, which fails to develop in normal females, is also absent in ARKO males. Force production is decreased from fast-twitch ARKO male muscle, and slow-twitch muscle has increased fatigue resistance. Microarray analysis shows up-regulation of genes encoding slow-twitch muscle contractile proteins. Real-time PCR confirms that expression of genes encoding polyamine biosynthetic enzymes, ornithine decarboxylase (Odc1), and S-adenosylmethionine decarboxylase (Amd1), is reduced in ARKO muscle, suggesting androgens act through regulation of polyamine biosynthesis. Altered expression of regulators of myoblast progression from proliferation to terminal differentiation suggests androgens also promote muscle growth by maintaining myoblasts in the proliferate state and delaying differentiation (increased Cdkn1c and Igf2, decreased Itg1bp3). A similar pattern of gene expression is observed in orchidectomized male mice, during androgen withdrawal-dependent muscle atrophy. In conclusion, androgens are not required for peak muscle mass in females. In males, androgens act through the AR to regulate multiple gene pathways that control muscle mass, strength, and fatigue resistance.