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Pain Hypersensitivity in a Mouse Model of Marfan Syndrome
Rebecca Kordikowski1,2, Joana Coutinho2,3, Ignacio Martínez-Martel1,2
1Grup de Neurofarmacologia Molecular, Institut de Recerca Sant Pau (IR SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain.
Abstract:
Marfan syndrome (MFS) is a genetic disorder caused by mutations in the fibrillin-1 (Fbn1) gene, leading to structurally abnormal elastic fibers and diverse clinical manifestations. Aortic root dilation represents the most serious threat, often requiring prophylactic surgical repair. Emerging evidence suggests that MFS patients experience increased pain sensitivity, contributing to functional impairment and reduced quality of life. Here, we used C57BL/6 wild-type and Fbn1C1041G/+ (MFS) mice to examine brain transcriptomics, aortic histology, nociceptive behaviors, grip strength, and spinal cord gene expression in both sexes at 2, 4, 6, 8, and 16 months of age. Transcriptomic analysis revealed reduced activation of pain-related pathways in young males and aged females, with a reversal in aged males, suggesting age- and sex-dependent differences in pain modulation. Behavioral testing showed progressive mechanical and thermal hypersensitivity in MFS mice, with cold allodynia as the earliest manifestation with late-onset muscle weakness. In the spinal cord of 16-month-old MFS mice, increased expression of key excitatory and nociceptive markers was observed, consistent with the pain hypersensitivity phenotype. In addition, aged female MFS mice exhibited elevated spinal expression of pro-inflammatory cytokines, inducible nitric oxide synthase, and Nox4, whereas males showed increased transforming growth factor-β1 and Nox1, reflecting distinct inflammatory and oxidative stress profiles. These findings demonstrate that Fbn1C1041G/+ mice reproduce pain hypersensitivity and muscle deficits observed in MFS patients, supporting their use as a preclinical model. Our results suggest that enhanced spinal excitatory/nociceptive signaling, together with neuroinflammation and oxidative stress, contributes to sex- and age-specific pain mechanisms in MFS.
Insights
Marfan syndrome (MFS) causes pain and muscle weakness due to fibrillin-1 gene mutations. This study reveals age- and sex-specific pain mechanisms in MFS mice, involving spinal cord changes.
Area of Science:
- Genetics and Molecular Biology
- Neuroscience
- Pathology
Background:
- Marfan syndrome (MFS) is a genetic disorder caused by fibrillin-1 (Fbn1) gene mutations, leading to connective tissue abnormalities.
- Aortic root dilation is a primary concern, but increased pain sensitivity and functional impairment are also reported in MFS patients.
- Understanding the underlying mechanisms of pain in MFS is crucial for improving patient quality of life.
Purpose of the Study:
- To investigate the age- and sex-dependent mechanisms of pain hypersensitivity and muscle deficits in a mouse model of Marfan syndrome (MFS).
- To analyze brain and spinal cord transcriptomics, nociceptive behaviors, and muscle strength in Fbn1-deficient mice.
Main Methods:
- Utilized C57BL/6 wild-type and Fbn1C1041G/+ (MFS) mice of both sexes across multiple ages (2-16 months).
- Conducted brain transcriptomics, aortic histology, behavioral testing for nociception and grip strength, and spinal cord gene expression analysis.
- Examined pain-related pathways, inflammatory markers, and oxidative stress indicators.
Main Results:
- MFS mice exhibited progressive mechanical and thermal hypersensitivity, with cold allodynia as an early sign, and developed late-onset muscle weakness.
- Transcriptomic analysis indicated age- and sex-dependent alterations in pain-related pathways.
- Spinal cord analysis revealed increased excitatory/nociceptive markers, pro-inflammatory cytokines, and oxidative stress markers, with distinct profiles in males and females.
Conclusions:
- The Fbn1C1041G/+ mouse model effectively replicates pain hypersensitivity and muscle deficits seen in Marfan syndrome patients.
- Enhanced spinal excitatory/nociceptive signaling, neuroinflammation, and oxidative stress contribute to sex- and age-specific pain mechanisms in MFS.
- These findings support the utility of this mouse model for preclinical studies and highlight potential therapeutic targets for pain management in MFS.
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