Author:
Margotta Cassandra,Fabbrizio Paola,Ceccanti Marco,Cambieri Chiara,Ruffolo Gabriele,D’Agostino Jessica,Trolese Maria Chiara,Cifelli Pierangelo,Alfano Veronica,Laurini Christian,Scaricamazza Silvia,Ferri Alberto,Sorarù Gianni,Palma Eleonora,Inghilleri Maurizio,Bendotti Caterina,Nardo Giovanni
Abstract
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.
Funder
Fondazione Italiana di Ricerca per la Sclerosi Laterale Amiotrofica
Regione Lombardia
Ministero della Salute
DISCAB 2022
Sapienza Università di Roma
Publisher
Springer Science and Business Media LLC
Subject
Immunology,Immunology and Allergy
Cited by
3 articles.
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