Oura Miya, Son Bo-Kyung, Song Zehan, Toyoshima Koichi, Nanao-Hamai Michiko, Ogawa Sumito, Akishita Masahiro
Department of Geriatric Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
Institute for Future Initiatives, Institute of Gerontology, The University of Tokyo, Engineering 8th Building 709, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
Sci Rep. 2025 Mar 27;15(1):10568. doi: 10.1038/s41598-025-95115-6.
Sarcopenia is caused by excessive muscle protein degradation owing to various factors, including disuse. Although testosterone supplementation is an effective treatment, the underlying molecular mechanisms, particularly the role of the androgen receptor (AR), remain unclear. In this study, we examined the preventive actions of testosterone/AR against muscle atrophy in a murine model of immobilization-induced muscle atrophy. The bilateral hindlimbs of 8-week-old male C57BL/6J mice were immobilized using a wire. Testosterone deficiency and supplementation (50 µg/mL) were conducted by castration and intraperitoneal injection (twice a week for a month), respectively. The results showed a remarkable decline in muscle mass and strength after wire-induced immobilization for 14 days. The expression of muscle atrophic factors (Atrogin1 and MuRF1) and inflammatory factors (F4/80 and interleukin-6 (IL-6)) significantly increased (p < 0.001). Notably, muscular AR expression significantly decreased, whereas myostatin and CCAAT/enhancer-binding protein delta (C/EBPδ), a transcriptional activator of myostatin, were significantly elevated (p < 0.05). After castration, AR expression further decreased, and muscular changes with wire-induced immobilization deteriorated. These exacerbations were completely ameliorated by testosterone supplementation and AR upregulation. Our study provides important therapeutic insights into testosterone/AR in muscular atrophy caused by immobilization and shows that muscular AR in a testosterone-dependent manner regulates C/EBPδ/myostatin and inflammation.
肌肉减少症是由包括废用在内的多种因素导致的肌肉蛋白质过度降解所引起的。尽管补充睾酮是一种有效的治疗方法，但其潜在的分子机制，尤其是雄激素受体（AR）的作用仍不清楚。在本研究中，我们在固定诱导的肌肉萎缩小鼠模型中研究了睾酮/AR对肌肉萎缩的预防作用。使用金属丝固定8周龄雄性C57BL/6J小鼠的双侧后肢。分别通过去势和腹腔注射（每周两次，持续一个月）造成睾酮缺乏和补充（50μg/mL）。结果显示，金属丝诱导固定14天后，肌肉质量和力量显著下降。肌肉萎缩因子（Atrogin1和MuRF1）和炎症因子（F4/80和白细胞介素-6（IL-6））的表达显著增加（p<0.001）。值得注意的是，肌肉AR表达显著降低，而肌生成抑制素和肌生成抑制素的转录激活因子CCAAT/增强子结合蛋白δ（C/EBPδ）显著升高（p<0.05）。去势后，AR表达进一步降低，金属丝诱导固定引起的肌肉变化恶化。补充睾酮和上调AR可完全改善这些恶化情况。我们的研究为睾酮/AR在固定引起的肌肉萎缩中的治疗提供了重要见解，并表明肌肉AR以睾酮依赖的方式调节C/EBPδ/肌生成抑制素和炎症。
