Immune-mediated myogenesis and acetylcholine receptor clustering promote a slow disease progression in ALS mouse models.

IF 5 3区 医学 Q2 IMMUNOLOGY
Cassandra Margotta, Paola Fabbrizio, Marco Ceccanti, Chiara Cambieri, Gabriele Ruffolo, Jessica D'Agostino, Maria Chiara Trolese, Pierangelo Cifelli, Veronica Alfano, Christian Laurini, Silvia Scaricamazza, Alberto Ferri, Gianni Sorarù, Eleonora Palma, Maurizio Inghilleri, Caterina Bendotti, Giovanni Nardo
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引用次数: 2

Abstract

Background: Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease in terms of onset and progression rate. This may account for therapeutic clinical trial failure. Transgenic SOD1G93A mice on C57 or 129Sv background have a slow and fast disease progression rate, mimicking the variability observed in patients. Based on evidence inferring the active influence of skeletal muscle on ALS pathogenesis, we explored whether dysregulation in hindlimb skeletal muscle reflects the phenotypic difference between the two mouse models.

Methods: Ex vivo immunohistochemical, biochemical, and biomolecular methodologies, together with in vivo electrophysiology and in vitro approaches on primary cells, were used to afford a comparative and longitudinal analysis of gastrocnemius medialis between fast- and slow-progressing ALS mice.

Results: We reported that slow-progressing mice counteracted muscle denervation atrophy by increasing acetylcholine receptor clustering, enhancing evoked currents, and preserving compound muscle action potential. This matched with prompt and sustained myogenesis, likely triggered by an early inflammatory response switching the infiltrated macrophages towards a M2 pro-regenerative phenotype. Conversely, upon denervation, fast-progressing mice failed to promptly activate a compensatory muscle response, exhibiting a rapidly progressive deterioration of muscle force.

Conclusions: Our findings further pinpoint the pivotal role of skeletal muscle in ALS, providing new insights into underestimated disease mechanisms occurring at the periphery and providing useful (diagnostic, prognostic, and mechanistic) information to facilitate the translation of cost-effective therapeutic strategies from the laboratory to the clinic.

Abstract Image

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免疫介导的肌发生和乙酰胆碱受体聚集促进ALS小鼠模型的缓慢疾病进展。
背景:肌萎缩性侧索硬化症(ALS)在发病和进展率方面是一种异质性疾病。这可能是治疗性临床试验失败的原因。C57或129Sv背景下的转基因SOD1G93A小鼠的疾病进展速度有慢有快,类似于在患者中观察到的变异性。基于骨骼肌对ALS发病机制的积极影响的证据,我们探讨了后肢骨骼肌的失调是否反映了两种小鼠模型的表型差异。方法:采用离体免疫组织化学、生物化学和生物分子方法,结合体内电生理学和体外原代细胞方法,对快速和缓慢进展的ALS小鼠腓肠肌内侧肌进行比较和纵向分析。结果:我们报道了进展缓慢的小鼠通过增加乙酰胆碱受体聚类、增强诱发电流和保持肌肉复合动作电位来抵消肌肉去神经支配萎缩。这与迅速和持续的肌生成相匹配,可能是由早期炎症反应触发的,将浸润的巨噬细胞转换为M2促再生表型。相反,在去神经支配时,快速发展的小鼠未能及时激活代偿肌肉反应,表现出肌肉力量的迅速进行性恶化。结论:我们的研究结果进一步明确了骨骼肌在ALS中的关键作用,为被低估的外围疾病机制提供了新的见解,并提供了有用的(诊断、预后和机制)信息,以促进从实验室到临床的成本效益治疗策略的转化。
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来源期刊
CiteScore
11.10
自引率
1.20%
发文量
45
审稿时长
11 weeks
期刊介绍: Inflammation and Regeneration is the official journal of the Japanese Society of Inflammation and Regeneration (JSIR). This journal provides an open access forum which covers a wide range of scientific topics in the basic and clinical researches on inflammation and regenerative medicine. It also covers investigations of infectious diseases, including COVID-19 and other emerging infectious diseases, which involve the inflammatory responses. Inflammation and Regeneration publishes papers in the following categories: research article, note, rapid communication, case report, review and clinical drug evaluation.
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