ABSTRACT

Purpose/Aim

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease characterized by extensive muscle weakness. Patients with DMD lack a functional dystrophin protein, which transmits force and organizes the cytoskeleton of skeletal muscle. Multiomic studies have been proposed as a way to obtain novel insight about disease processes from preclinical models, and we used this approach to study pathological changes in dystrophic muscles.

Materials and Methods

We evaluated hindlimb muscles of male mdx/mTR mice, which lack a functional dystrophin protein and have deficits in satellite cell abundance and proliferative capacity. Wild type (WT) C57BL/6 J mice served as controls. Muscle fiber contractility was measured, along with changes in the transcriptome using RNA sequencing, and in the proteome, metabolome, and lipidome using mass spectrometry.

Results

While mdx/mTR mice displayed gross pathological changes and continued cycles of degeneration and regeneration, we found no differences in permeabilized fiber contractility between strains. However, there were numerous changes in the transcriptome and proteome related to protein balance, contractile elements, extracellular matrix, and metabolism. There was only a 53% agreement in fold-change data between the proteome and transcriptome. Numerous changes in markers of skeletal muscle metabolism were observed, with dystrophic muscles exhibiting elevated glycolytic metabolites such as 6-phosphoglycerate, fructose-6-phosphate and glucose-6-phosphate, fructose bisphosphate, phosphorylated hexoses, and phosphoenolpyruvate.

Conclusions

These findings highlight the utility of multiomics in studying muscle disease, and provide additional insight into the pathological changes in dystrophic muscles that might help to indirectly guide evidence-based nutritional or exercise prescription in DMD patients.

中文翻译：

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杜氏肌营养不良症 mdx/mTR 小鼠模型的多组学分析。

摘要

目的/目标

杜氏肌营养不良症 (DMD) 是一种进行性神经肌肉疾病，其特征是广泛的肌肉无力。DMD 患者缺乏功能性肌营养不良蛋白，该蛋白可传递力并组织骨骼肌的细胞骨架。已经提出多组学研究作为从临床前模型中获得有关疾病过程的新见解的一种方式，我们使用这种方法来研究营养不良肌肉的病理变化。

材料和方法

我们评估了雄性 mdx/mTR 小鼠的后肢肌肉，这些小鼠缺乏功能性肌营养不良蛋白，并且在卫星细胞丰度和增殖能力方面存在缺陷。野生型 (WT) C57BL/6 J 小鼠作为对照。使用 RNA 测序测量肌肉纤维收缩性以及转录组的变化，以及使用质谱法测量蛋白质组、代谢组和脂质组的变化。

结果

虽然 mdx/mTR 小鼠表现出严重的病理变化和持续的退化和再生循环，但我们发现菌株之间的透化纤维收缩性没有差异。然而，与蛋白质平衡、收缩元件、细胞外基质和代谢相关的转录组和蛋白质组发生了许多变化。蛋白质组和转录组之间的倍数变化数据只有 53% 的一致性。观察到骨骼肌代谢标志物的许多变化，营养不良的肌肉表现出升高的糖酵解代谢物，例如 6-磷酸甘油酸、6-磷酸果糖和 6-磷酸葡萄糖、二磷酸果糖、磷酸化己糖和磷酸烯醇式丙酮酸。

结论

这些发现突出了多组学在研究肌肉疾病中的效用，并提供了对营养不良肌肉病理变化的进一步了解，这可能有助于间接指导 DMD 患者的循证营养或运动处方。