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Sunitinib-mediated inhibition of STAT3 in skeletal muscle and spinal cord does not affect the disease in a mouse model of ALS.
- Source :
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Neurobiology of disease [Neurobiol Dis] 2024 Sep; Vol. 199, pp. 106576. Date of Electronic Publication: 2024 Jun 22. - Publication Year :
- 2024
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Abstract
- 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.<br />Competing Interests: Declaration of competing interest The authors declare no competing interest.<br /> (Copyright © 2024. Published by Elsevier Inc.)
- Subjects :
- Animals
Mice
Superoxide Dismutase metabolism
Superoxide Dismutase genetics
Muscular Atrophy metabolism
Muscular Atrophy pathology
Motor Neurons drug effects
Motor Neurons metabolism
Motor Neurons pathology
Disease Progression
Amyotrophic Lateral Sclerosis metabolism
Amyotrophic Lateral Sclerosis drug therapy
Amyotrophic Lateral Sclerosis pathology
Sunitinib pharmacology
Muscle, Skeletal drug effects
Muscle, Skeletal metabolism
Muscle, Skeletal pathology
STAT3 Transcription Factor metabolism
STAT3 Transcription Factor antagonists & inhibitors
Mice, Transgenic
Indoles pharmacology
Disease Models, Animal
Spinal Cord metabolism
Spinal Cord drug effects
Spinal Cord pathology
Mice, Inbred C57BL
Pyrroles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1095-953X
- Volume :
- 199
- Database :
- MEDLINE
- Journal :
- Neurobiology of disease
- Publication Type :
- Academic Journal
- Accession number :
- 38914173
- Full Text :
- https://doi.org/10.1016/j.nbd.2024.106576