面岬肱肌营养不良症患者的肌肉蛋白质组分析揭示了促进氧化/还原应激的代谢重构,导致肌肉功能丧失。

IF 6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Manuela Moriggi, Lucia Ruggiero, Enrica Torretta, Dario Zoppi, Beatrice Arosio, Evelyn Ferri, Alessandra Castegna, Chiara Fiorillo, Cecilia Gelfi, Daniele Capitanio
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引用次数: 0

摘要

面胛肱骨肌营养不良症(FSHD)是由双同源染色体 4(DUX4)基因的表观遗传去抑制引起的,导致不对称肌无力和萎缩,从面部和肩胛肌肉开始,逐渐发展到下肢。这种无法治愈的疾病会严重损害肌肉功能,最终导致丧失行走能力。目前还缺乏对与FSHD不同程度的肌肉损伤相关的分子因素的透彻分析。本研究根据 FSHD 临床评分、A-B-C-D 分类方案和全球蛋白质组变异,研究了 FSHD 患者肱二头肌的分子机制和生物标志物。我们的研究结果揭示了患者不同的代谢特征和代偿反应。在严重病例中,我们观察到明显的代谢功能障碍,其特征是糖酵解失调、磷酸戊糖还原途径(PPP)激活、向还原性 TCA 循环转变、氧化磷酸化受抑制,以及抗氧化剂过量产生,但其功能所需的氧化还原辅因子却没有相应增加。这种失衡最终导致还原压力,加剧肌肉萎缩和炎症。与此相反,轻度病例会出现新陈代谢适应性变化,通过激活多元醇和氧化 PPP 来减轻压力,通过氧化 TCA 循环保持部分能量流,从而支持线粒体功能和能量平衡。此外,激活己糖胺生物合成途径可促进自噬,保护肌肉细胞免于凋亡。总之,我们的蛋白质组数据表明,轻度和重度FSHD患者都存在特定的代谢改变。在轻度病例中发现的分子可能是FSHD的潜在诊断和治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Muscle Proteome Analysis of Facioscapulohumeral Dystrophy Patients Reveals a Metabolic Rewiring Promoting Oxidative/Reductive Stress Contributing to the Loss of Muscle Function.

Facioscapulohumeral muscular dystrophy (FSHD) is caused by the epigenetic de-repression of the double homeobox 4 (DUX4) gene, leading to asymmetric muscle weakness and atrophy that begins in the facial and scapular muscles and progresses to the lower limbs. This incurable condition can severely impair muscle function, ultimately resulting in a loss of ambulation. A thorough analysis of molecular factors associated with the varying degrees of muscle impairment in FSHD is still lacking. This study investigates the molecular mechanisms and biomarkers in the biceps brachii of FSHD patients, classified according to the FSHD clinical score, the A-B-C-D classification scheme, and global proteomic variation. Our findings reveal distinct metabolic signatures and compensatory responses in patients. In severe cases, we observe pronounced metabolic dysfunction, marked by dysregulated glycolysis, activation of the reductive pentose phosphate pathway (PPP), a shift toward a reductive TCA cycle, suppression of oxidative phosphorylation, and an overproduction of antioxidants that is not matched by an increase in the redox cofactors needed for their function. This imbalance culminates in reductive stress, exacerbating muscle wasting and inflammation. In contrast, mild cases show metabolic adaptations that mitigate stress by activating polyols and the oxidative PPP, preserving partial energy flow through the oxidative TCA cycle, which supports mitochondrial function and energy balance. Furthermore, activation of the hexosamine biosynthetic pathway promotes autophagy, protecting muscle cells from apoptosis. In conclusion, our proteomic data indicate that specific metabolic alterations characterize both mild and severe FSHD patients. Molecules identified in mild cases may represent potential diagnostic and therapeutic targets for FSHD.

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来源期刊
Antioxidants
Antioxidants Biochemistry, Genetics and Molecular Biology-Physiology
CiteScore
10.60
自引率
11.40%
发文量
2123
审稿时长
16.3 days
期刊介绍: Antioxidants (ISSN 2076-3921), provides an advanced forum for studies related to the science and technology of antioxidants. It publishes research papers, reviews and communications. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced. Electronic files and software regarding the full details of the calculation or experimental procedure, if unable to be published in a normal way, can be deposited as supplementary electronic material.
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