Aerobic exercise ameliorates skeletal muscle atrophy in atic knockout zebrafish through the oxidative phosphorylation pathway.

IF 7.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Zheng Peng, Tianle Yang, Siting Xu, Boyu Yang, Zhilong Zhang, Meng Ding, Wenzhi Gu, Lan Zheng
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引用次数: 0

Abstract

The mechanisms linking purine metabolism disorders to skeletal muscle pathology are unclear. This study constructed a CRISPR/Cas9-mediated zebrafish atic knockout model and a siRNA-interfered C2C12 myoblast cell model. We revealed a novel mechanism by which ATIC (5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase) deletion drove the atrophy of skeletal muscle through the downregulation of the oxidative phosphorylation of mitochondria (OXPHOS) pathway. It was found that atic/Atic knockout/knockdown led to the interruption of purine de novo synthesis, abnormal 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) accumulation, and blockage of inosine monophosphate (IMP) synthesis, which in turn triggered mitochondrial structural damage, dysfunction of complex I-V function, and a burst of reactive oxygen species (ROS), and ultimately triggered muscle atrophy through activation of the ubiquitin-proteasome system. The progressive aerobic intervention revealed that 8 weeks of training significantly restored skeletal muscle function in zebrafish atic-/- mutants, and the mechanism was related to the enhancement of mitochondrial biogenesis, up-regulation of the core complex expression of the OXPHOS pathway, and the improvement of ROS scavenging ability. These findings reveal that ATIC deficiency disrupts mitochondrial function through purine metabolism dysregulation, linking aberrant AICAR accumulation to OXPHOS impairment, which provides a theoretical basis for the early warning of muscular toxicity of targeted purine metabolizing drugs and lays a molecular foundation for the exercise rehabilitation strategy of metabolic myopathies.

有氧运动通过氧化磷酸化途径改善atic敲除斑马鱼骨骼肌萎缩。
嘌呤代谢紊乱与骨骼肌病理之间的联系机制尚不清楚。本研究构建了CRISPR/ cas9介导的斑马鱼基因敲除模型和sirna干扰的C2C12成肌细胞模型。我们揭示了ATIC(5-氨基咪唑-4-羧酰胺核糖核苷酸甲酰转移酶/IMP环水解酶)缺失通过下调线粒体氧化磷酸化(OXPHOS)途径驱动骨骼肌萎缩的新机制。研究发现,atic/ atic敲除/敲低导致嘌呤新生合成中断,5-氨基咪唑-4-羧酰胺核糖核苷酸(AICAR)积累异常,肌苷单磷酸(IMP)合成受阻,进而引发线粒体结构损伤、复合体I-V功能障碍和活性氧(ROS)爆发,最终通过激活泛素-蛋白酶体系统引发肌肉萎缩。渐进式有氧干预显示,8周的训练显著恢复了斑马鱼atic-/-突变体的骨骼肌功能,其机制与线粒体生物发生增强、OXPHOS通路核心复合物表达上调、ROS清除能力提高有关。这些发现表明ATIC缺乏通过嘌呤代谢失调破坏线粒体功能,将AICAR异常积累与OXPHOS损伤联系起来,为靶向嘌呤代谢药物的肌肉毒性预警提供了理论依据,为代谢性肌病的运动康复策略奠定了分子基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Free Radical Biology and Medicine
Free Radical Biology and Medicine 医学-内分泌学与代谢
CiteScore
14.00
自引率
4.10%
发文量
850
审稿时长
22 days
期刊介绍: Free Radical Biology and Medicine is a leading journal in the field of redox biology, which is the study of the role of reactive oxygen species (ROS) and other oxidizing agents in biological systems. The journal serves as a premier forum for publishing innovative and groundbreaking research that explores the redox biology of health and disease, covering a wide range of topics and disciplines. Free Radical Biology and Medicine also commissions Special Issues that highlight recent advances in both basic and clinical research, with a particular emphasis on the mechanisms underlying altered metabolism and redox signaling. These Special Issues aim to provide a focused platform for the latest research in the field, fostering collaboration and knowledge exchange among researchers and clinicians.
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