3,3'-二吲哚甲烷通过调节线粒体功能和钙稳态改善肌肉萎缩
3,3'-Diindolylmethane ameliorates muscle atrophy by modulating mitochondrial function and calcium homeostasis.
摘要(中文译文)
肌少症是一种以肌肉质量和功能进行性丧失为特征的慢性退行性疾病。目前的治疗策略疗效有限，且在确保患者持续依从性方面面临重大挑战。尽管线粒体功能障碍已被证实是骨骼肌萎缩的生物标志物，但调控该过程的确切分子机制尚未完全阐明。值得注意的是，钙库操纵性钙内流（SOCE）不仅是线粒体钙信号传导中的关键机制，而且近年来已被确定为肌少症的重要促成因素。3,3'-二吲哚甲烷（DIM）的新型制剂显示出改善的药代动力学特征，副作用极小且生物利用度高，从而提高了治疗依从性。然而，既往研究尚未完全揭示DIM治疗肌少症的治疗潜力或其精确分子机制。本研究通过三种研究模型系统探讨DIM对肌少症的治疗效果，并分层阐明其潜在分子机制。我们采用了三种不同的模型：长期注射地塞米松（DEX）诱导的小鼠肌肉萎缩模型、秀丽隐杆线虫（C. elegans）自然衰老模型，以及地塞米松干预的C2C12肌管萎缩细胞模型。主要评价指标包括组织病理学检查、免疫荧光、荧光探针、蛋白质印迹和流式细胞术。DIM通过增强小鼠握力和肌纤维质量、延长秀丽隐杆线虫寿命，展现出治疗潜力。DIM减轻了DEX诱导的肌管萎缩，同时促进肌管分化。在机制上，DIM通过抑制肌肉萎缩引起的活性氧过度生成和线粒体膜电位下降来缓解线粒体功能障碍。同时，DIM增强基质相互作用分子1的表达以激活SOCE，从而调节钙稳态并促进肌肉细胞分化，有效防止进一步的肌肉萎缩。重要的是，本研究首次在三种不同的实验模型（小鼠肌肉萎缩、秀丽隐杆线虫和细胞系统）中证明，DIM通过改善线粒体功能来激活和增强SOCE机制，从而恢复紊乱的钙稳态并减轻肌肉萎缩。这些发现为天然植物化学物质如何对抗肌少症提供了新的机制见解和有前景的干预靶点，同时强调了DIM在缓解肌肉萎缩方面的治疗潜力。
Abstract
Sarcopenia is a chronic degenerative condition characterized by the progressive loss of muscle mass and function. Current therapeutic strategies exhibit limited therapeutic efficacy and present substantial challenges in ensuring sustained patient compliance. Although mitochondrial dysfunction is a confirmed biomarker of skeletal muscle atrophy, the exact molecular mechanisms governing this process have yet to be fully elucidated. Notably, store-operated calcium entry (SOCE) not only serves as a pivotal mechanism in mitochondrial calcium signaling but has also been recently identified as a key contributor to sarcopenia. Novel formulations of 3,3'-Diindolylmethane (DIM) shows improved pharmacokinetics with minimal side effects and high bioavailability, thereby enhancing therapeutic adherence. However, previous studies have not fully unraveled the therapeutic potential of DIM for managing sarcopenia or its precise molecular mechanisms. This research was conducted to systematically explore the therapeutic efficacy of DIM in sarcopenia through three research models and hierarchically clarify the underlying molecular mechanisms. We used three distinct models: a murine model of muscle atrophy induced by long-term injection of dexamethasone (DEX), a worm model of natural aging in Caenorhabditis elegans (C. elegans), and a cell model of C2C12 myotube atrophy intervened by dexamethasone. The primary evaluation measures encompassed histopathological examination, immunofluorescence, fluorescent probes, western blot and flow cytometry. DIM demonstrated therapeutic promise by enhancing grip strength and myofiber quality in mice, extending lifespan of C. elegans. DIM attenuated DEX-induced myotube atrophy while promoting myotube differentiation. Mechanistically, DIM mitigated mitochondrial dysfunction by inhibiting excessive reactive oxygen species generation and decline of mitochondrial membrane potential caused by muscle atrophy. Concurrently, DIM enhanced the expression of stromal interaction molecule 1 to activate SOCE, thereby modulating calcium homeostasis and promoting muscle cell differentiation, effectively preventing further muscle atrophy. Importantly, this study constitutes the inaugural demonstration across three distinct experimental models (murine muscle atrophy, Caenorhabditis elegans and cellular systems) that DIM activates and enhances the SOCE mechanism by improving mitochondrial function, thereby restoring disrupted calcium homeostasis and alleviating muscle atrophy. These findings offer novel mechanistic insights and promising intervention targets regarding how natural phytochemicals counteract sarcopenia, while concurrently underscoring the therapeutic potential of DIM in alleviating muscle atrophy.
如何引用
AMA
Xing Gao, Xin Feng, Guoquan Feng, Jianjun Zhong, Yingying Liu, Sitong Pan, et al. 3,3'-Diindolylmethane ameliorates muscle atrophy by modulating mitochondrial function and calcium homeostasis.. Phytomedicine : international journal of phytotherapy and phytopharmacology. 2026; doi:10.1016/j.phymed.2026.158409.
APA
Xing Gao, Xin Feng, Guoquan Feng, Jianjun Zhong, Yingying Liu, Sitong Pan, et al (2026). 3,3'-Diindolylmethane ameliorates muscle atrophy by modulating mitochondrial function and calcium homeostasis.. Phytomedicine : international journal of phytotherapy and phytopharmacology. https://doi.org/10.1016/j.phymed.2026.158409
GB/T 7714
Xing Gao, Xin Feng, Guoquan Feng, Jianjun Zhong, Yingying Liu, Sitong Pan, et al. 3,3'-Diindolylmethane ameliorates muscle atrophy by modulating mitochondrial function and calcium homeostasis.[J]. Phytomedicine : international journal of phytotherapy and phytopharmacology, 2026 doi:10.1016/j.phymed.2026.158409.
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