Département des Sciences Fondamentales, Université du Québec à Chicoutimi, Saguenay, QC, Canada.
Groupe de Recherche Interdisciplinaire sur les Maladies Neuromusculaires (GRIMN), Centre Intégré Universitaire de Santé et de Services Sociaux du Saguenay-Lac-Saint-Jean, Saguenay, QC, Canada.
J Neuromuscul Dis. 2024;11(5):981-995. doi: 10.3233/JND-230139.
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.
Identifying physiopathological markers related to maximal strength loss over time in DM1.
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.
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).
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.
1 型肌强直性营养不良（DM1）是一种由肌强直性营养不良蛋白激酶（DMPK）基因上异常的 CTG 重复引起的进行性疾病。来自 CTG 重复的长 mRNA 在核灶中稳定，并隔离肌肉盲样剪接调节因子 1（MBNL1）。DM1 的主要特征包括肌肉萎缩和无力。DM1 进展对骨骼肌的影响研究不足。
确定与 DM1 患者随时间推移最大力量丧失相关的生理病理学标志物。
22 名 DM1 患者参加了两次膝关节伸肌的最大等长肌肉力量（MIMS）评估和两次股外侧肌活检，间隔 3 年。评估肌纤维类型、大小（包括最小 Feret 直径 [MFD] 和萎缩/肥大因子 [AF/HF]）以及核灶和 MBNL1 共定位（灶/MBNL1+）。免疫印迹用于测量糖原合酶激酶-3β（GSK3β）、p62、LC3BI、LC3BII 和氧化磷酸化蛋白。
MIMS 的倍数变化与 1 型纤维 MFD（ρ=0.483）和 AF（ρ=-0.514）呈显著相关。回归分析表明，基线灶/MBNL1+核百分比和力量训练可解释 44.1%的灶/MBNL1+核百分比随时间的变化。MIMS 的倍数变化与 GSK3β（ρ=0.327）、p62（ρ=0.473）、LC3BI（ρ=0.518）、LC3BII（ρ=-0.391）和 LC3BII/LC3BI（ρ=-0.773）呈良好的相关性。
1 型 MFD 减少和 AF 增加与 MIMS 丧失相关。灶/MBNL1+核的积累似乎存在平台效应，而力量训练有助于减少这种积累。自噬标志物 LC3BII/LC3BI 比值具有很好的 MIMS 丧失的生物标志物潜力，但需要进一步研究。
