Sunitinib-mediated inhibition of STAT3 in skeletal muscle and spinal cord does not affect the disease in a mouse model of ALS.

Autor: Tortarolo M; Research Center for ALS, Dept. Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milano, Italy., Re Cecconi AD; Research Center for ALS, Dept. Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milano, Italy., Camporeale L; Research Center for ALS, Dept. Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milano, Italy., Margotta C; Research Center for ALS, Dept. Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milano, Italy., Nardo G; Research Center for ALS, Dept. Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milano, Italy., Pasetto L; Research Center for ALS, Dept. Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milano, Italy., Bonetto V; Research Center for ALS, Dept. Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milano, Italy., Galbiati M; Dipartimento di Scienze Farmacologiche e Biomolecolari 'Rodolfo Paoletti', Dipartimento di Eccellenza 2018-2027, Università degli Studi di Milano, via Balzaretti 9, 20133 Milano, Italy., Crippa V; Dipartimento di Scienze Farmacologiche e Biomolecolari 'Rodolfo Paoletti', Dipartimento di Eccellenza 2018-2027, Università degli Studi di Milano, via Balzaretti 9, 20133 Milano, Italy., Poletti A; Dipartimento di Scienze Farmacologiche e Biomolecolari 'Rodolfo Paoletti', Dipartimento di Eccellenza 2018-2027, Università degli Studi di Milano, via Balzaretti 9, 20133 Milano, Italy., Piccirillo R; Research Center for ALS, Dept. Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milano, Italy., Bendotti C; Research Center for ALS, Dept. Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Via Mario Negri 2, 20156 Milano, Italy. Electronic address: caterina.bendotti@marionegri.it.
Jazyk: angličtina
Zdroj: Neurobiology of disease [Neurobiol Dis] 2024 Sep; Vol. 199, pp. 106576. Date of Electronic Publication: 2024 Jun 22.
DOI: 10.1016/j.nbd.2024.106576
Abstrakt: Variability in disease onset and progression is a hallmark of amyotrophic lateral sclerosis (ALS), both in sporadic and genetic forms. Recently, we found that SOD1-G93A transgenic mice expressing the same amount of mutant SOD1 but with different genetic backgrounds, C57BL/6JOlaHsd and 129S2/SvHsd, show slow and rapid muscle wasting and disease progression, respectively. Here, we investigated the different molecular mechanisms underlying muscle atrophy. Although both strains showed similar denervation-induced degradation of muscle proteins, only the rapidly progressing mice exhibited early and sustained STAT3 activation that preceded atrophy in gastrocnemius muscle. We therefore investigated the therapeutic potential of sunitinib, a tyrosine kinase inhibitor known to inhibit STAT3 and prevent cancer-induced muscle wasting. Although sunitinib treatment reduced STAT3 activation in the gastrocnemius muscle and lumbar spinal cord, it did not preserve spinal motor neurons, improve neuromuscular impairment, muscle atrophy and disease progression in the rapidly progressing SOD1-G93A mice. Thus, the effect of sunitinib is not equally positive in different diseases associated with muscle wasting. Moreover, given the complex role of STAT3 in the peripheral and central compartments of the neuromuscular system, the present study suggests that its broad inhibition may lead to opposing effects, ultimately preventing a potential positive therapeutic action in ALS.
Competing Interests: Declaration of competing interest The authors declare no competing interest.
(Copyright © 2024. Published by Elsevier Inc.)
Databáze: MEDLINE
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