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Low energy availability reduces bone mass and gonadal function in male mice

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Abstract

Introduction

In women, the female athlete triad, marked by low energy availability, functional hypothalamic amenorrhea and osteoporosis, is a recognized risk for stress fractures. Stress injuries also occur in men, but by contrast risks and mechanisms underlying them are less characterized.

Materials and methods

5 week-old wild-type male mice were fed ad libitum (ad) or subjected to 60% food restriction (FR) for five weeks. In both groups, some mice were allowed access to an exercise wheel in cages to allow voluntary wheel running (ex) and/or treated with active vitamin D analogues. Mice were sacrificed and analyzed at 10 weeks of age.

Result

Male FR mice exhibited significantly reduced testicle weight, serum testosterone levels and bone mass. Such bone losses in FR male mice were enhanced by exercise. Histological analysis revealed that both bone-resorbing and -forming activities were significantly reduced in FR or FR plus exercise (FR + ex) mice, mimicking a state of low bone turnover. Significantly reduced bone mass in FR or FR + ex male mice was significantly rescued by treatment with active vitamin D analogues, with significant restoration of osteoblastic activities. Serum levels of insulin-like growth factor I (IGF-I), which is critical for bone remodeling, were significantly lower in FR versus control male mice.

Conclusions

Low energy availability puts men at risk for stress injuries as well, and low energy availability is upstream of gonadal dysfunction and osteoporosis in males. Active vitamin D analogues could serve as therapeutic or preventive options for stress injuries in men.

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Acknowledgements

T. Miyamoto was supported by a grant-in-aid for Scientific Research in Japan and a grant from the Japan Agency for Medical Research and Development. Y. Sato and K. Miyamoto were supported by a grant-in-aid for Scientific Research in Japan.

Author information

Authors and Affiliations

  1. Institute for Integrated Sports Medicine, Keio University School of Medicine, 35 Shinano-Machi, Shinjuku-Ku, Tokyo, 160-8582, Japan

    Eri Ito, Hideo Matsumoto & Kazuki Sato

  2. Department of Orthopedic Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Yuiko Sato, Tami Kobayashi, Tatsuaki Matsumoto, Atushi Kimura, Morio Matsumoto, Masaya Nakamura & Takeshi Miyamoto

  3. Department of Advanced Therapy for Musculoskeletal Disorders II, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Yuiko Sato, Tami Kobayashi & Takeshi Miyamoto

  4. Department of Musculoskeletal Reconstruction and Regeneration Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Yuiko Sato, Tami Kobayashi & Takeshi Miyamoto

  5. Division of Oral and Maxillofacial Surgery, Department of Dentistry and Oral Surgery, Keio University School of Medicine, 35 Shinano-machi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Tomoya Soma

  6. Department of Orthopedic Surgery, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan

    Kana Miyamoto & Takeshi Miyamoto

Authors
  1. Eri Ito
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  2. Yuiko Sato
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  3. Tami Kobayashi
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  5. Tatsuaki Matsumoto
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  8. Hideo Matsumoto
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  10. Masaya Nakamura
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  11. Kazuki Sato
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  12. Takeshi Miyamoto
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Contributions

EI and TM (Miyamoto) conceived the study. EI conducted the study. EI, YS and TK provided experimental mice. EI collected and analyzed data. EI, TS, TM (Matsumoto), AK, KM and TM (Miyamoto) interpreted data. HM, MM, MN, KS and TM (Miyamoto) supervised the study. EI and TM (Miyamoto) wrote the manuscript. All authors approved the manuscript. EI takes responsibility for the integrity of the data analysis.

Corresponding authors

Correspondence to Kazuki Sato or Takeshi Miyamoto.

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The authors declare that they have no conflicts of interest with the contents of this article.

Ethical statement

All animal protocols were approved by the Keio University Institutional Animal Care and Use Committee. All animal experiments were conducted by the Institutional Guidelines on Animal Experimentation at Keio University (approval number 09092).

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Ito, E., Sato, Y., Kobayashi, T. et al. Low energy availability reduces bone mass and gonadal function in male mice. J Bone Miner Metab 41, 182–192 (2023). https://doi.org/10.1007/s00774-023-01413-2

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