Contrasting Becker and Duchenne muscular dystrophy serum biomarker candidates by using data independent acquisition LC-MS/MS.

IF 5.3 2区医学 Q2 CELL BIOLOGY

Skeletal Muscle Pub Date : 2025-06-07 DOI:10.1186/s13395-025-00385-3

Camilla Johansson, Esther J Schrama, David Kotol, Andreas Hober, Zaïda Koeks, Nienke M van de Velde, Jan J G M Verschuuren, Erik H Niks, Fredrik Edfors, Pietro Spitali, Cristina Al-Khalili Szigyarto

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引用次数: 0

Abstract

Background: Becker muscular dystrophy (BMD) is a rare and heterogeneous form of dystrophinopathy caused by expression of altered dystrophin proteins, as a consequence of in-frame genetic mutations. The majority of the BMD biomarker studies employ targeted approaches and focus on translating findings from Duchenne Muscular Dystrophy (DMD), a more severe disease form with clinical similarities but caused by out-of-frame mutations in the dystrophin gene. Importantly, DMD therapies assume that disease progression can be slowed by promoting the expression of truncated dystrophin comparable to what occurs in BMD patients. In this study, we explore similarities and differences in protein trajectories over time between BMD and DMD serum, and explore proteins related to motor function performance.

Methods: Serum samples collected from 34 BMD patients, in a prospective longitudinal 3-year study, and 19 DMD patients, were analyzed by using Data Independent Acquisition Tandem Mass Spectrometry (DIA-MS). Subsequent normalization, linear mixed effects model was employed to identify proteins associated with physical tests and dystrophin expression in skeletal muscle. Analysis was also performed to explore the discrepancy between DMD and BMD biomarker abundance trajectories over time.

Results: Linear mixed effects models identified 20 proteins with altered longitudinal signatures between DMD and BMD, including creatine kinase M-type (CKM) pyruvate kinase (PKM), fibrinogen gamma chain (FGG), lactate dehydrogenase B (LDHB) and alpha-2-macroglobulin (A2M). Furthermore, several proteins related to innate immune response were associated with motor function in BMD patients. In particular, A2M displayed an altered time-dependent decline in relation to dystrophin expression in the tibialis anterior muscle.

Conclusions: Our study revealed differences in the serum proteome between BMD and DMD, which comprises proteins involved in the immune response, extracellular matrix organization and hemostasis but not muscle leakage proteins significantly associated with disease progression in DMD. If further evaluated and validated, these biomarker candidates may offer means to monitor disease progression in BMD patients. A2M is of particular interest due to its association with dystrophin expression in BMD muscle and higher abundance in DMD patients in comparison to BMD. If validated, A2M could be used as a pharmacodynamic biomarker in therapeutic clinical trials aiming to restore dystrophin expression.

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采用数据独立采集LC-MS/MS对比Becker和Duchenne肌营养不良症血清生物标志物候选物。

背景：贝克肌营养不良症（BMD）是一种罕见且异质性的肌营养不良症，由肌营养不良蛋白表达改变引起，是框架内基因突变的结果。大多数BMD生物标志物研究采用针对性的方法，并专注于翻译杜氏肌营养不良症（DMD）的发现，这是一种更严重的疾病形式，具有临床相似性，但由肌营养不良蛋白基因的框外突变引起。重要的是，DMD治疗假设可以通过促进截断的肌营养不良蛋白的表达来减缓疾病的进展，这与BMD患者的情况类似。在这项研究中，我们探索了BMD和DMD血清中蛋白质轨迹随时间的异同，并探索了与运动功能表现相关的蛋白质。方法：采用数据独立获取串联质谱法（DIA-MS）对34例BMD患者和19例DMD患者的血清样本进行分析。随后归一化，采用线性混合效应模型鉴定骨骼肌中与体格测试和肌营养不良蛋白表达相关的蛋白质。分析还探讨了DMD和BMD生物标志物丰度轨迹随时间的差异。结果：线性混合效应模型确定了20种蛋白在DMD和BMD之间的纵向特征发生改变，包括肌酸激酶m型（CKM）、丙酮酸激酶（PKM）、纤维蛋白原γ链（FGG）、乳酸脱氢酶B （LDHB）和α -2巨球蛋白（A2M）。此外，一些与先天免疫反应相关的蛋白质与骨密度下降患者的运动功能有关。特别是，A2M表现出与胫骨前肌中肌营养不良蛋白表达有关的改变的时间依赖性下降。结论：我们的研究揭示了BMD和DMD之间血清蛋白质组的差异，其中包括参与免疫反应、细胞外基质组织和止血的蛋白质，但不包括与DMD疾病进展显著相关的肌肉渗漏蛋白。如果进一步评估和验证，这些候选生物标志物可能为监测骨密度患者的疾病进展提供手段。由于A2M与骨骼肌中肌营养不良蛋白的表达有关，并且与骨骼肌相比，A2M在DMD患者中表达的丰度更高，因此引起了人们的特别关注。如果得到验证，A2M可以作为一种药效学生物标志物用于旨在恢复肌营养不良蛋白表达的治疗性临床试验。

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

Skeletal Muscle CELL BIOLOGY-

CiteScore

9.10

自引率

0.00%

发文量

审稿时长

12 weeks

期刊介绍： The only open access journal in its field, Skeletal Muscle publishes novel, cutting-edge research and technological advancements that investigate the molecular mechanisms underlying the biology of skeletal muscle. Reflecting the breadth of research in this area, the journal welcomes manuscripts about the development, metabolism, the regulation of mass and function, aging, degeneration, dystrophy and regeneration of skeletal muscle, with an emphasis on understanding adult skeletal muscle, its maintenance, and its interactions with non-muscle cell types and regulatory modulators. Main areas of interest include: -differentiation of skeletal muscle- atrophy and hypertrophy of skeletal muscle- aging of skeletal muscle- regeneration and degeneration of skeletal muscle- biology of satellite and satellite-like cells- dystrophic degeneration of skeletal muscle- energy and glucose homeostasis in skeletal muscle- non-dystrophic genetic diseases of skeletal muscle, such as Spinal Muscular Atrophy and myopathies- maintenance of neuromuscular junctions- roles of ryanodine receptors and calcium signaling in skeletal muscle- roles of nuclear receptors in skeletal muscle- roles of GPCRs and GPCR signaling in skeletal muscle- other relevant aspects of skeletal muscle biology. In addition, articles on translational clinical studies that address molecular and cellular mechanisms of skeletal muscle will be published. Case reports are also encouraged for submission. Skeletal Muscle reflects the breadth of research on skeletal muscle and bridges gaps between diverse areas of science for example cardiac cell biology and neurobiology, which share common features with respect to cell differentiation, excitatory membranes, cell-cell communication, and maintenance. Suitable articles are model and mechanism-driven, and apply statistical principles where appropriate; purely descriptive studies are of lesser interest.