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

Inflammation and Regeneration

Research Article

Pierangelo Cifelli¹  Chiara Cambieri²  Marco Ceccanti²  Christian Laurini²  Maurizio Inghilleri²  Gianni Sorarù³  Silvia Scaricamazza⁴  Alberto Ferri⁵  Veronica Alfano⁶  Eleonora Palma⁷  Gabriele Ruffolo⁷  Caterina Bendotti⁸  Cassandra Margotta⁸  Maria Chiara Trolese⁸  Paola Fabbrizio⁸  Giovanni Nardo⁸  Jessica D’Agostino⁸ 

[1]Department of Applied Clinical and Biotechnological Sciences, University of L’Aquila, 67100, L’Aquila, Italy

[2]Department of Human Neurosciences, Rare Neuromuscular Diseases Centre, Sapienza University of Rome, 00185, Rome, Italy

[3]Department of Neuroscience, Azienda Ospedaliera di Padova, Via Giustiniani 2, 35128, Padua, Italy

[4]IRCCS Fondazione Santa Lucia, Rome, Italy

[5]IRCCS Fondazione Santa Lucia, Rome, Italy

[6]Institute of Translational Pharmacology (IFT-CNR), Rome, Italy

[7]IRCCS San Raffaele Roma, 00163, Rome, Italy

[8]Laboratory Affiliated to Istituto Pasteur Italia, Department of Physiology and Pharmacology, Sapienza University of Rome, 00185, Rome, Italy

[9]IRCCS San Raffaele Roma, 00163, Rome, Italy

[10]Laboratory of Molecular Neurobiology, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156, Milan, Italy

关键词: Amyotrophic lateral sclerosis;    Mouse model;    ACh receptor;    Skeletal muscle;    Macrophages;    Myogenesis;    Satellite cells;   

DOI  :  10.1186/s41232-023-00270-w

 received in 2022-12-23, accepted in 2023-02-25,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundAmyotrophic 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.MethodsEx 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.ResultsWe 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.ConclusionsOur 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.

【 授权许可】

CC BY   
© The Author(s) 2023. corrected publication 2023

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