Impaired skeletal muscle development and function in male, but not female, genomic androgen receptor knockout mice
Abstract
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. Realtime 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 Igf 2, 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. FASEB J. 22, 2676–2689 (2008)
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Androgen action, represented by circulating testosterone, is the key determinant of the higher muscle mass and strength characteristic of males compared with females.
“This indicates that androgen action, represented by circulating testosterone, is the key determinant of the higher muscle mass and strength characteristic of males compared with females.”
From Circulating Testosterone as the Hormonal Basis of Sex Differences in Athletic Performance (2018) · cites this paper as [101]
In AR-null males, force production decreases in fast-twitch fibers, whereas fatigue resistance increases in slow-twitch fibers to levels similar to wild-type females.
“Additionally, in AR-null males, force production decreases in fast-twitch fibers, whereas fatigue resistance increases in slow-twitch fibers to levels similar to wild-type females (59).”
From Sex-Based Differences in Skeletal Muscle Kinetics and Fiber-Type Composition (2015) · cites this paper as [59]
Male AR-null mice have a decrease in muscle mass that is not seen in AR-null females.
“Male AR-null mice have a decrease in muscle mass that is not seen in AR-null females (59).”
From Sex-Based Differences in Skeletal Muscle Kinetics and Fiber-Type Composition (2015) · cites this paper as [59]
Analysis of mRNA reveals an upregulation of genes encoding slow-twitch muscle contractile proteins in AR-null mice.
“Analysis of mRNA reveals an upregulation of genes encoding slow-twitch muscle contractile proteins in AR-null mice (2, 59).”
From Sex-Based Differences in Skeletal Muscle Kinetics and Fiber-Type Composition (2015) · cites this paper as [59]
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- Authors
- MacLean, H. E., Chiu, W. S. M., Notini, A. J., Axell, A.-M., Davey, R. A., McManus, J. F., Ma, C., Plant, D. R., Lynch, G. S., & Zajac, J. D.
- Affiliations
- The University of Melbourne (AU)
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2008-04-07
- Volume
- 22
- Issue
- 8
- Pages
- 2676-2689
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W1984242978
- Cited by
- 209
- References
- 42
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 13 · 2023: 16 · 2022: 8 · 2021: 9 · 2020: 8 · 2019: 13 · 2018: 16 · 2017: 13 · 2016: 10 · 2015: 13 · 2014: 17 · 2013: 4 · 2012: 6
- FWCI
- 6.30
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Health and Medical Research Council (350334, 359226)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Keywords
- androgen receptor, skeletal muscle development, muscle mass, sex differences, levator ani muscle, muscle fatigue resistance, slow-twitch muscle, polyamine biosynthesis, ornithine decarboxylase, S-adenosylmethionine decarboxylase, myogenesis, CDKN1C, insulin-like growth factor II, androgen withdrawal, muscle atrophy
- MeSH terms
- Androgens, Animals, Cell Differentiation, Female, Male, Mice, Inbred C57BL, Muscle Contraction, Orchiectomy, Organ Size, Receptors, Androgen, Sex Characteristics, Testis, Gene Expression, Mice, Knockout, Muscle, Skeletal, Muscle Fibers, Fast-Twitch, Muscle Fibers, Slow-Twitch, Myoblasts, Skeletal, Cell Proliferation, Mice, Gene Regulatory Networks
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