Reduced Bone Mass and Muscle Strength in Male 5α-Reductase Type 1 Inactivated Mice
Open accessAbstract
Androgens are important regulators of bone mass but the relative importance of testosterone (T) versus dihydrotestosterone (DHT) for the activation of the androgen receptor (AR) in bone is unknown. 5α-reductase is responsible for the irreversible conversion of T to the more potent AR activator DHT. There are two well established isoenzymes of 5α-reductase (type 1 and type 2), encoded by separate genes (Srd5a1 and Srd5a2). 5α-reductase type 2 is predominantly expressed in male reproductive tissues whereas 5α-reductase type 1 is highly expressed in liver and moderately expressed in several other tissues including bone. The aim of the present study was to investigate the role of 5α-reductase type 1 for bone mass using Srd5a1⁻/⁻ mice. Four-month-old male Srd5a1⁻/⁻ mice had reduced trabecular bone mineral density (-36%, p<0.05) and cortical bone mineral content (-15%, p<0.05) but unchanged serum androgen levels compared with wild type (WT) mice. The cortical bone dimensions were reduced in the male Srd5a1⁻/⁻ mice as a result of a reduced cortical periosteal circumference compared with WT mice. T treatment increased the cortical periosteal circumference (p<0.05) in orchidectomized WT mice but not in orchidectomized Srd5a1⁻/⁻ mice. Male Srd5a1⁻/⁻ mice demonstrated a reduced forelimb muscle grip strength compared with WT mice (p<0.05). Female Srd5a1⁻/⁻ mice had slightly increased cortical bone mass associated with elevated circulating levels of androgens. In conclusion, 5α-reductase type 1 inactivated male mice have reduced bone mass and forelimb muscle grip strength and we propose that these effects are due to lack of 5α-reductase type 1 expression in bone and muscle. In contrast, the increased cortical bone mass in female Srd5a1⁻/⁻ mice, is an indirect effect mediated by elevated circulating androgen levels.
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There have been several reports of 5αR type 1 KO mice with no reports of altered fat including in gonadal depots.
“There have been also several reports of 5αR type 1 KO mice with no reports of altered fat 176 including in gonadal depots.”
From The role of the androgen receptor in the pathogenesis of obesity and its utility as a target for obesity treatments (2022) · cites this paper as [177]
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“There have been also several reports of 5αR type 1 KO mice with no reports of altered fat(176) including in gonadal depots.(177) The only piece”
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“In fact, Srd5a1 KO mice showed the abnormalities in these behaviors (10–12), and also partial feminization of the male skeleton (13).”
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Androgen and estrogen actions on male physical activity: a story beyond muscle
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Muscle atrophy induced by overexpression of ALAS2 is related to muscle mitochondrial dysfunction
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“SRD5A1 global knock-out mice exhibit reduced androgen levels, suggesting that targeting SRD5A1 may be a potential therapeutic strategy for managing PCOS [39].”
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- Authors
- Windahl, S. H., Andersson, N., Börjesson, A. E., Swanson, C., Svensson, J., Movérare-Skrtic, S., Sjögren, K., Shao, R., Lagerquist, M. K., & Ohlsson, C.
- Affiliations
- University of Gothenburg (SE)
- Corresponding author
- Ohlsson, Claes
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-06-22
- Volume
- 6
- Issue
- 6
- Pages
- e21402
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3120862
- OpenAlex
- W2098615121
- Cited by
- 56
- References
- 41
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 6 · 2020: 5 · 2019: 3 · 2018: 3 · 2017: 3 · 2016: 5 · 2015: 5 · 2014: 2 · 2013: 6 · 2012: 7
- FWCI
- 5.11
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (publishedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Chalmers Research (Chalmers University of Technology) (submittedVersion)
- Funders
- Stiftelsen för Strategisk Forskning
- Novo Nordisk
- Vetenskapsrådet
- Magnus Bergvalls Stiftelse
- Novo Nordisk Fonden
- National Institutes of Health (DK071122)
- National Institute of Diabetes and Digestive and Kidney Diseases (R56DK071122, R01DK071122, DK-071122)
- Topics
- Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone health and osteoporosis research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Keywords
- 5α-reductase type 1, bone mass, trabecular bone mineral density, cortical bone, muscle strength, grip strength, androgens, testosterone, dihydrotestosterone, androgen receptor, sex differences
- MeSH terms
- Androgens, Animals, Body Weight, Bone and Bones, Enzyme Activation, Female, Forelimb, Isoenzymes, Male, Membrane Proteins, Orchiectomy, Organ Size, Ovary, Receptors, Prolactin, RNA, Messenger, Testosterone, 3-Oxo-5-alpha-Steroid 4-Dehydrogenase, Viscera, Bone Density, Mice, Knockout, Hand Strength, Gene Expression Profiling, Mice, Muscle Strength
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