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

Helen MacLean, W S Maria Chiu, Amanda Notini, Anna-Maree Axell, Rachel Davey, Julie McManus, Cathy Ma, David Plant, Gordon Lynch, Jeffrey Zajac

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128 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)2676 - 2689
Number of pages14
JournalThe FASEB Journal
Volume22
Issue number8
DOIs
Publication statusPublished - 2008
Externally publishedYes

Cite this

MacLean, H., Chiu, W. S. M., Notini, A., Axell, A-M., Davey, R., McManus, J., Ma, C., Plant, D., Lynch, G., & Zajac, J. (2008). Impaired skeletal muscle development and function in male, but not female, genomic androgen receptor knockout mice. The FASEB Journal, 22(8), 2676 - 2689. https://doi.org/10.1096/fj.08-105726