XLOC_015548通过Gadd45g/MEK/ERK通路和氧化还原调控缓解骨骼肌萎缩。

IF 3.3 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Tiantian Qi, Haotian Qin, Fei Yu, Zimeng Zhou, Yingqi Chen, Peng Liu, Hui Zeng, Jian Weng
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引用次数: 0

摘要

背景:骨骼肌萎缩是一种常见的肌肉骨骼疾病,显著降低患者的生活质量。长链非编码RNA (lncRNA) XLOC_015548已被鉴定为C2C12成肌细胞增殖和分化的关键调节因子。然而,其在减轻去神经支配引起的肌肉萎缩中的作用及其潜在机制尚不清楚。方法:采用慢病毒介导的XLOC_015548在C2C12成肌细胞和骨骼肌特异性XLOC_015548编辑小鼠模型中的稳定表达,研究该lncRNA的功能。体外采用地塞米松诱导的糖皮质激素萎缩模型,体内采用坐骨神经横断诱导的去神经支配模型。MEK抑制剂U0126用于评估生长停滞和DNA损伤诱导的45 γ /丝裂原活化蛋白激酶/细胞外信号调节激酶(Gadd45g/MEK/ERK)信号通路的作用。结果:过表达XLOC_015548通过下调Gadd45g表达(p < 0.05),促进其胞质定位,显著激活MEK/ERK信号通路(p < 0.05),从而促进细胞增殖和肌管形成。此外,XLOC_015548降低了活性氧(ROS)水平(p < 0.01),稳定了线粒体膜电位,减轻了dex诱导的氧化应激。这些保护作用被U0126部分逆转,证实了MEK/ERK通路的参与。体内骨骼肌特异性过表达XLOC_015548显著降低去神经支配诱导的肌肉萎缩(q < 0.05),增加肌纤维横截面积。结论:XLOC_015548通过调节Gadd45g的表达,激活MEK/ERK信号通路,降低氧化应激,在促进成肌分化和防止肌肉萎缩中发挥关键作用。这些发现强调了XLOC_015548在骨骼肌萎缩中的治疗潜力,并为基于lncrna的治疗策略提供了基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
XLOC_015548 Mitigates Skeletal Muscle Atrophy via the Gadd45g/MEK/ERK Pathway and Redox Regulation.

Background: Skeletal muscle atrophy is a common musculoskeletal disorder that significantly reduces patient quality of life. Long non-coding RNA (lncRNA) XLOC_015548 has been identified as a pivotal regulator of C2C12 myoblast proliferation and differentiation. However, its role in mitigating denervation-induced muscle atrophy and the underlying mechanisms remain unclear.

Methods: We employed lentiviral-mediated stable expression of XLOC_015548 in C2C12 myoblasts and skeletal muscle-specific XLOC_015548-edited mouse models to investigate the function of this lncRNA. Muscle atrophy models were established in vitro by glucocorticoid-induced atrophy with dexamethasone (DEX) and in vivo by sciatic nerve transection-induced denervation. The MEK inhibitor U0126 was used to assess the role of the growth arrest and DNA damage-inducible 45 gamma/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (Gadd45g/MEK/ERK) signaling pathway.

Results: Overexpression of XLOC_015548 significantly activated the MEK/ERK signaling pathway (p < 0.05) by downregulating Gadd45g expression (p < 0.05) and promoting its cytoplasmic localization, thereby enhancing cell proliferation and myotube formation. Furthermore, XLOC_015548 reduced the level of reactive oxygen species (ROS) (p < 0.01), stabilized the mitochondrial membrane potential, and alleviated DEX-induced oxidative stress. These protective effects were partially reversed by U0126, confirming the involvement of the MEK/ERK pathway. Skeletal muscle-specific overexpression of XLOC_015548 in vivo significantly reduced denervation-induced muscle atrophy (q < 0.05) and increased the muscle fiber cross-sectional area.

Conclusion: XLOC_015548 plays a critical role in promoting myogenic differentiation and protecting against muscle atrophy by regulating Gadd45g expression, activating the MEK/ERK signaling pathway, and reducing oxidative stress. These findings underscore the therapeutic potential of XLOC_015548 in skeletal muscle atrophy, and provide a foundation for lncRNA-based treatment strategies.

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