Iannibelli Eliana, Ruggieri Alessandra, Maruotti Antonello, Salerno Franco, Cheli Marta, Carnazzi Alessandra, Nicolini De Gaetano Lucia, Riolo Giorgia, Bortolani Sara, Riguzzi Pietro, Vianello Sara, Merlonghi Gioia, Bello Luca, Garibaldi Matteo, Filosto Massimiliano, Previtali Stefano Carlo, Tasca Giorgio, Vattemi Gaetano, Tonin Paola, Pegoraro Elena, Gibertini Sara, Maggi Lorenzo
Department of Neuroimmunology and Neuromuscular Diseases, Fondazione IRCCS Neurological Institute Carlo Besta, Muscle Cell Biology Lab, Via Amadeo 42, 20133, Milano, Italy.
Department of Law, Economics, Politics and Modern Languages, LUMSA University, Rome, Italy.
Acta Neuropathol Commun. 2025 May 24;13(1):115. doi: 10.1186/s40478-025-02041-9.
Myofibrillar Myopathies (MFMs) are a growing group of muscular disorders genetically determined, whose diagnosis is based on histological features as myofibrillar degeneration, Z-disk disorganization and protein aggregates' accumulation. Protein aggregates that do not fit the proteasome's narrow pore are targeted for removal via a specialized form of autophagy, called aggrephagy. Our study aims to investigate the potential pathogenic role of aggrephagy in 52 muscle samples from an Italian MFM multicentric cohort. We measured, the percentage of positive areas of key aggrephagy proteins by immunofluorescence staining, of sequestosome 1 (p62/SQSTM1), Neighbor of BRCA1 Gene 1 (NBR1), and ubiquitinated proteins (FK2) in 11 DES-, 6 DNAJB6-, 5 FLNC-, 18 MYOT- and 12 TTN-mutated patients. We showed that all aggrephagy markers are increased in these patients, regardless of the mutated genes, suggesting a possible common pathomechanism; no positive signal was found in healthy, age-matched controls. We analyzed the association between positivity levels of these markers, measured as percentage of positive areas, and selected clinical features utilizing generalized linear mixed models with gamma distribution as the probability model and center-specific random effects to better capture possible heterogeneity across participating centers. Our findings indicate significant associations between levels of p62, NBR1, and FK2 with age at biopsy (p62 and NBR1 p-values < 0.001, FK2 p-value < 0.05), age of onset (p62 and NBR1 p-values < 0.001, FK2 p-value < 0.01) and disease severity through Walton & Gardner-Medwin (WGM) score at biopsy (all p-values < 0.001) and at the last visit (all p-values < 0.05). Noteworthy, the aggrephagic pathway is mostly activated in MYOT-mutated patients compared to the other subgroups. Moreover, the association between aggrephagy and WGM score at biopsy is stronger in this subgroup. Overall, our study emphasizes the role of aggrephagy in MFMs across all patients, and its association with specific clinical parameters.
肌原纤维肌病（MFMs）是一组日益增多的由基因决定的肌肉疾病，其诊断基于组织学特征，如肌原纤维变性、Z盘紊乱和蛋白质聚集体的积累。不符合蛋白酶体狭窄孔径的蛋白质聚集体会通过一种特殊形式的自噬（称为聚集体自噬）被靶向清除。我们的研究旨在调查聚集体自噬在来自意大利MFMs多中心队列的52个肌肉样本中的潜在致病作用。我们通过免疫荧光染色测量了11例肌动蛋白解聚因子（DES）突变、6例DNAJB6突变、5例细丝蛋白C（FLNC）突变、18例肌联蛋白（MYOT）突变和12例肌联蛋白（TTN）突变患者中关键聚集体自噬蛋白（包括聚集体自噬受体蛋白p62/ sequestosome 1、BRCA1基因邻域蛋白1（NBR1）和泛素化蛋白（FK2））的阳性区域百分比。我们发现，无论突变基因如何，所有这些患者中的聚集体自噬标记物均增加，这表明可能存在共同的病理机制；在年龄匹配的健康对照中未发现阳性信号。我们使用以伽马分布作为概率模型并具有中心特异性随机效应的广义线性混合模型，分析了这些标记物的阳性水平（以阳性区域百分比衡量）与选定临床特征之间的关联，以更好地捕捉各参与中心之间可能存在的异质性。我们的研究结果表明，p62、NBR1和FK2的水平与活检时的年龄（p62和NBR1的p值<0.001，FK2的p值<0.05）、发病年龄（p62和NBR1的p值<0.001，FK2的p值<0.01）以及通过沃尔顿和加德纳 - 梅德温（WGM）评分评估的活检时（所有p值<0.001）和最后一次随访时（所有p值<0.05）的疾病严重程度之间存在显著关联。值得注意的是，与其他亚组相比，聚集体自噬途径在MYOT突变患者中激活程度最高。此外，在该亚组中，活检时聚集体自噬与WGM评分之间的关联更强。总体而言，我们的研究强调了聚集体自噬在所有MFMs患者中的作用及其与特定临床参数的关联。
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