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Impaired skeletal muscle development and function in male, but not female, genomic androgen receptor knockout mice

Helen E. MacLean^*, W. S. Maria Chiu^*, Amanda J. Notini^*, Anna-Maree Axell^*, Rachel A. Davey^*, Julie F. McManus^*, Cathy Ma^*, David R. Plant, Gordon S. Lynch and Jeffrey D. Zajac^*

^* Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia; and

Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia

¹Correspondence: Austin Hospital, Heidelberg, VIC 3084, Australia. E-mail: hmaclean{at}unimelb.edu.au

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.—MacLean, H. E., Maria Chiu, W. S., Notini, A. J., Axell, A.-M., Davey, R. A., McManus, J. F., Ma, C., Plant, D. R., Lynch, G. S., Zajac, J. D. Impaired skeletal muscle development and function in male, but not female, genomic androgen receptor knockout mice.

Key Words: hypertrophy • anabolic • knockout • strength • polyamine

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