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Chikungunya and Mayaro Viruses Induce Chronic Skeletal Muscle Atrophy Triggered by Pro-Inflammatory and Oxidative
Mariana Oliveira Lopes da Silva1, Camila Menezes Figueiredo1, Rômulo Leão Silva Neris1
1Department of Virology, Instituto de Microbiologia Paulo de Góes, Universidade Federal do Rio de Janeiro (UFRJ), Rio de Janeiro 21941-902, Brazil.
Abstract:
Chikungunya (CHIKV) and Mayaro (MAYV) viruses are arthritogenic alphaviruses that promote an incapacitating and long-lasting inflammatory muscle-articular disease. Despite studies pointing out the importance of skeletal muscle (SkM) in viral pathogenesis, the long-term consequences on its physiology and the mechanism of persistence of symptoms are still poorly understood. Combining molecular, morphological, nuclear magnetic resonance imaging, and histological analysis, we conduct a temporal investigation of CHIKV and MAYV replication in a wild-type mice model, focusing on the impact on SkM composition, structure, and repair in the acute and late phases of infection. We found that viral replication and induced inflammation promote a rapid loss of muscle mass and reduction in fiber cross-sectional area by upregulation of muscle-specific E3 ubiquitin ligases MuRF1 and Atrogin-1 expression, both key regulators of SkM fibers atrophy. Despite a reduction in inflammation and clearance of infectious viral particles, SkM atrophy persists until 30 days post-infection. The genomic CHIKV and MAYV RNAs were still detected in SkM in the late phase, along with the upregulation of chemokines and anti-inflammatory cytokine expression. In agreement with the involvement of inflammatory mediators on induced atrophy, the neutralization of TNF and a reduction in oxidative stress using monomethyl fumarate, an agonist of Nrf2, decreases atrogen expression and atrophic fibers while increasing weight gain in treated mice. These data indicate that arthritogenic alphavirus infection could chronically impact body SkM composition and also harm repair machinery, contributing to a better understanding of mechanisms of arthritogenic alphavirus pathogenesis and with a description of potentially new targets of therapeutic intervention.
Insights
Chikungunya and Mayaro viruses cause long-lasting muscle pain. Viral RNA persists in muscle, causing atrophy even after infection clears, highlighting potential therapeutic targets.
Area of Science:
- Virology
- Immunology
- Skeletal Muscle Physiology
Background:
- Chikungunya (CHIKV) and Mayaro (MAYV) are arthritogenic alphaviruses causing persistent inflammatory muscle-articular disease.
- The long-term effects of CHIKV and MAYV on skeletal muscle (SkM) and symptom persistence remain poorly understood.
- Skeletal muscle plays a critical role in the pathogenesis of these viral infections.
Purpose of the Study:
- To investigate the temporal impact of CHIKV and MAYV infection on skeletal muscle composition, structure, and repair.
- To elucidate the mechanisms underlying long-term skeletal muscle atrophy following alphavirus infection.
- To identify potential therapeutic targets for mitigating CHIKV and MAYV-induced muscle pathology.
Main Methods:
- Temporal investigation of CHIKV and MAYV replication in a wild-type mice model.
- Utilized molecular, morphological, nuclear magnetic resonance imaging, and histological analyses.
- Assessed viral RNA persistence, muscle atrophy markers (MuRF1, Atrogin-1), inflammatory mediators (TNF), and oxidative stress (Nrf2).
Main Results:
- Viral replication and inflammation led to rapid muscle mass loss and reduced fiber cross-sectional area via MuRF1 and Atrogin-1 upregulation.
- Skeletal muscle atrophy persisted for 30 days post-infection, despite reduced inflammation and viral clearance.
- Genomic CHIKV and MAYV RNAs were detected in SkM late in infection, with elevated chemokine and anti-inflammatory cytokine expression.
- TNF neutralization and Nrf2 activation (monomethyl fumarate) reduced atrophy and increased weight gain.
Conclusions:
- Arthritogenic alphavirus infections can chronically impact skeletal muscle composition and impair muscle repair mechanisms.
- Persistent viral RNA and inflammatory mediators contribute to long-term muscle atrophy.
- Targeting TNF and oxidative stress pathways presents a potential therapeutic strategy for alphavirus-induced myopathy.
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