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

Autor: Margotta C; Laboratory of Molecular Neurobiology, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156, Milan, Italy., Fabbrizio P; Laboratory of Molecular Neurobiology, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156, Milan, Italy., Ceccanti M; Department of Human Neurosciences, Rare Neuromuscular Diseases Centre, Sapienza University of Rome, 00185, Rome, Italy., Cambieri C; Department of Human Neurosciences, Rare Neuromuscular Diseases Centre, Sapienza University of Rome, 00185, Rome, Italy., Ruffolo G; Laboratory Affiliated to Istituto Pasteur Italia, Department of Physiology and Pharmacology, Sapienza University of Rome, 00185, Rome, Italy.; IRCCS San Raffaele Roma, 00163, Rome, Italy., D'Agostino J; Laboratory of Molecular Neurobiology, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156, Milan, Italy., Trolese MC; Laboratory of Molecular Neurobiology, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156, Milan, Italy., Cifelli P; Department of Applied Clinical and Biotechnological Sciences, University of L'Aquila, 67100, L'Aquila, Italy., Alfano V; IRCCS San Raffaele Roma, 00163, Rome, Italy., Laurini C; Department of Human Neurosciences, Rare Neuromuscular Diseases Centre, Sapienza University of Rome, 00185, Rome, Italy., Scaricamazza S; IRCCS Fondazione Santa Lucia, Rome, Italy., Ferri A; IRCCS Fondazione Santa Lucia, Rome, Italy.; Institute of Translational Pharmacology (IFT-CNR), Rome, Italy., Sorarù G; Department of Neuroscience, Azienda Ospedaliera di Padova, Via Giustiniani 2, 35128, Padua, Italy., Palma E; Laboratory Affiliated to Istituto Pasteur Italia, Department of Physiology and Pharmacology, Sapienza University of Rome, 00185, Rome, Italy.; IRCCS San Raffaele Roma, 00163, Rome, Italy., Inghilleri M; Department of Human Neurosciences, Rare Neuromuscular Diseases Centre, Sapienza University of Rome, 00185, Rome, Italy., Bendotti C; Laboratory of Molecular Neurobiology, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156, Milan, Italy. caterina.bendotti@marionegri.it., Nardo G; Laboratory of Molecular Neurobiology, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156, Milan, Italy.
Jazyk: angličtina
Zdroj: Inflammation and regeneration [Inflamm Regen] 2023 Mar 09; Vol. 43 (1), pp. 19. Date of Electronic Publication: 2023 Mar 09.
DOI: 10.1186/s41232-023-00270-w
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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