Changes in Physiopathological Markers in Myotonic Dystrophy Type 1 Skeletal Muscle: A 3-Year Follow-up Study.

IF 3.2 4区医学 Q2 CLINICAL NEUROLOGY

Journal of neuromuscular diseases Pub Date : 2024-01-01 DOI:10.3233/JND-230139

Marie-Pier Roussel, Aymeric Ravel-Chapuis, Jonathan Gobin, Bernard J Jasmin, Jean-Philippe Leduc-Gaudet, Cynthia Gagnon, Elise Duchesne

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引用次数: 0

Abstract

Background: Myotonic dystrophy type 1 (DM1) is a slowly progressive disease caused by abnormal CTG repetitions on the dystrophia myotonica protein kinase (DMPK) gene. Long mRNA from CTG repetitions stabilizes in nuclear foci and sequester muscleblind-like splicing regulator 1 (MBNL1). Cardinal signs of DM1 include muscle wasting and weakness. The impacts of DM1 progression on skeletal muscle are under-researched.

Objective: Identifying physiopathological markers related to maximal strength loss over time in DM1.

Methods: Twenty-two individuals with DM1 participated in two maximal isometric muscle strength (MIMS) evaluations of their knee extensors and two vastus lateralis muscle biopsies, 3 years apart. Muscle fiber typing, size (including minimal Feret's diameter [MFD] and atrophy/hypertrophy factors [AF/HF]), and nuclear foci and MBNL1 colocalization (foci/MBNL1+) were evaluated. Immunoblotting was used to measure glycogen synthase kinase-3 beta (GSK3β), p62, LC3BI, LC3BII, and oxidative phosphorylation proteins.

Results: There are significant correlations between the fold changes of MIMS with type 1 fiber MFD (ρ= 0.483) and AF (ρ= -0.514). Regression analysis shows that baseline percentage of foci/MBNL1+ nuclei and strength training explain 44.1% of foci/MBNL1+ nuclei percentage variation over time. There are fair to excellent correlations between the fold changes of MIMS and GSK3β (ρ= 0.327), p62 (ρ= 0.473), LC3BI (ρ= 0.518), LC3BII (ρ= -0.391) and LC3BII/LC3BI (ρ= -0.773).

Conclusion: Type 1 MFD decrease and AF increase are correlated with MIMS loss. There seems to be a plateau effect in foci/MBNL1+ nuclei accumulation and strength training helps decrease this accumulation. Autophagy marker LC3BII/LC3BI ratio has a good biomarker potential of MIMS loss, but more investigations are needed.

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肌营养不良症 1 型骨骼肌生理病理标志物的变化：三年跟踪研究

背景：肌营养不良症1型（DM1）是一种缓慢进展性疾病，由肌营养不良症蛋白激酶（DMPK）基因上的异常CTG重复引起。CTG重复的长mRNA会稳定在核病灶中，并封存肌束样剪接调节因子1（MBNL1）。DM1 的主要表现包括肌肉萎缩和无力。有关 DM1 进展对骨骼肌的影响的研究尚不充分：方法：22 名 DM1 患者参加了该研究：22名DM1患者参加了两次膝关节伸肌最大等长肌力（MIMS）评估和两次侧阔肌活检，两次评估相隔3年。对肌肉纤维类型、大小（包括最小费氏直径 [MFD] 和萎缩/肥大因子 [AF/HF]）以及核病灶和 MBNL1 共定位（病灶/MBNL1+）进行了评估。免疫印迹法用于检测糖原合成酶激酶-3 beta（GSK3β）、p62、LC3BI、LC3BII 和氧化磷酸化蛋白：MIMS 的折叠变化与 1 型纤维 MFD（ρ= 0.483）和房颤（ρ= -0.514）之间存在显着相关性。回归分析表明，病灶/MBNL1+ 核的基线百分比和力量训练可解释病灶/MBNL1+ 核百分比随时间变化的 44.1%。MIMS与GSK3β (ρ= 0.327)、p62 (ρ= 0.473)、LC3BI (ρ= 0.518)、LC3BII (ρ= -0.391)和LC3BII/LC3BI (ρ= -0.773)的折叠变化之间存在一般到极好的相关性：结论：1 型中频下降和房颤增加与 MIMS 下降相关。病灶/MBNL1+细胞核的积累似乎存在高原效应，而力量训练有助于减少这种积累。自噬标记物 LC3BII/LC3BI 比值具有良好的生物标记潜力，但还需要更多的研究。

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来源期刊

Journal of neuromuscular diseases Medicine-Neurology (clinical)

CiteScore

5.10

自引率

6.10%

发文量

102

期刊介绍： The Journal of Neuromuscular Diseases aims to facilitate progress in understanding the molecular genetics/correlates, pathogenesis, pharmacology, diagnosis and treatment of acquired and genetic neuromuscular diseases (including muscular dystrophy, myasthenia gravis, spinal muscular atrophy, neuropathies, myopathies, myotonias and myositis). The journal publishes research reports, reviews, short communications, letters-to-the-editor, and will consider research that has negative findings. The journal is dedicated to providing an open forum for original research in basic science, translational and clinical research that will improve our fundamental understanding and lead to effective treatments of neuromuscular diseases.