Kim Kyung Min, Oh Ho Taek, Do Youjin, Yoo Gi Don, Heo Woong, Park Jeekeon, Yang Hyejin, Yoon Suh Jin, Byun Mi Ran, Hwang Eun Sook, Hong Jeong-Ho
Division of Life Sciences, Korea University, Seoul, South Korea.
College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Woman's University, Seoul, South Korea.
J Cachexia Sarcopenia Muscle. 2025 Apr;16(2):e13790. doi: 10.1002/jcsm.13790.
Glucocorticoid therapy has a beneficial effect in several diseases, but chronic treatment has adverse effects, including muscle atrophy, which refers to the gradual decrease in muscle mass, size and strength. It is important to know how the muscle atrophy occurs, but the underlying mechanism is not yet fully understood. This study shows that dexamethasone decreases levels of the transcriptional co-activator with PDZ binding motif (TAZ), which facilitates dexamethasone-induced muscle atrophy.
To induce muscle atrophy, C2C12 myotubes were treated with dexamethasone, and mice were fed with water containing dexamethasone. Muscle atrophy was analysed for the expression of myosin heavy chain, MuRF1 and Atrogin-1 using immunofluorescence staining, immunoblot analysis and qRT-PCR. Muscle tissue was analysed by haematoxylin and eosin staining. Adeno-associated virus was used for overexpression of wild-type and mutant TAZ.
TAZ levels decrease in dexamethasone-treated mice (0.36-fold, p < 0.001) and C2C12 myotubes (0.44-fold, p = 0.024). Overexpression of the TAZ mutant, which resists its proteolytic degradation, inhibits dexamethasone-induced muscle atrophy. Atrogin-1 and MuRF1 interact with TAZ and facilitate its degradation in dexamethasone-treated C2C12 myotubes. TAZ mutant stimulates protein synthesis through activation of mTOR signalling via induction of RhebL1 (DEX; Con vs, TAZ4SA: 5.1-fold, p < 0.001) in dexamethasone-treated mice. Ginsenoside Rb3 increases TAZ levels in dexamethasone-treated mice (1.49-fold, p = 0.007) and C2C12 myotubes (1.63-fold, p = 0.01), which stimulates mTOR signalling and inhibits dexamethasone-induced muscle atrophy.
Our results demonstrate a novel regulatory mechanism of dexamethasone-induced muscle atrophy by TAZ, suggesting that stabilisation of TAZ in muscle cells ameliorates the muscle atrophy. These results suggest that TAZ may be a drug target for the dexamethasone-induced muscle atrophy.
糖皮质激素疗法在多种疾病中具有有益作用，但长期治疗会产生不良反应，包括肌肉萎缩，即肌肉质量、大小和力量的逐渐下降。了解肌肉萎缩的发生机制很重要，但其潜在机制尚未完全明确。本研究表明，地塞米松会降低具有PDZ结合基序的转录共激活因子（TAZ）的水平，而这会促进地塞米松诱导的肌肉萎缩。
为诱导肌肉萎缩，用 地塞米松处理 C2C12 肌管，并给小鼠饮用含地塞米松的水。使用免疫荧光染色、免疫印迹分析和 qRT-PCR 分析肌球蛋白重链、MuRF1 和 Atrogin-1 的表达以评估肌肉萎缩情况。用苏木精和伊红染色分析肌肉组织。腺相关病毒用于野生型和突变型 TAZ 的过表达。
在用地塞米松处理的小鼠（0.36 倍，p < 0.001）和 C2C12 肌管（0.44 倍，p = 0.024）中，TAZ 水平降低。抗蛋白水解降解的 TAZ 突变体的过表达可抑制地塞米松诱导的肌肉萎缩。在用地塞米松处理的 C2C12 肌管中，Atrogin-1 和 MuRF1 与 TAZ 相互作用并促进其降解。TAZ 突变体通过诱导 RhebL1 激活 mTOR 信号通路来刺激蛋白质合成（地塞米松处理的小鼠中，DEX；对照组与 TAZ4SA 组相比：5.1 倍，p < 0.001）。人参皂苷 Rb3 可提高用地塞米松处理的小鼠（1.49 倍，p = 0.007）和 C2C12 肌管（1.63 倍，p = 0.01）中的 TAZ 水平，这会刺激 mTOR 信号通路并抑制地塞米松诱导的肌肉萎缩。
我们的结果证明了TAZ对 地塞米松诱导的肌肉萎缩有新的调节机制，表明稳定肌肉细胞中的TAZ可改善肌肉萎缩。这些结果表明TAZ可能是地塞米松诱导的肌肉萎缩的药物靶点。
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