Persistent sarcopenia after flare remission in experimental RA responds to dipyridamole and is associated with restoration of adenosine and A2BR signaling
4 affiliations
- 1Joint and Bone Research Unit, FIIS-Fundación Jiménez Díaz UAM
- 2PhD Program in Medicine and Surgery, Universidad Autónoma
- 3Ocupharm Group Research, Faculty of Optic and Optometry, University Complutense of Madrid
- 4Department of Optometry and Vision, Faculty of Optic and Optometry, University Complutense of Madrid
Abstract
Introduction: Rheumatoid arthritis (RA) is associated with systemic inflammation and sarcopenia, which often persist despite successful control of joint swelling and the mechanisms sustaining it remain unclear.
Methods: Using the K/BxN serum-transfer model, we evaluated muscle structure, metabolism, and function after inflammatory remission. Dipyridamole was administered after remission of joint swelling to assess whether enhancement of adenosine and adenosine receptor signaling restore muscle homeostasis. Histological, molecular, metabolic, and functional analyses were performed.
Results: RA mice exhibited persistent loss of muscle mass, fiber atrophy, fibrosis, white adipose tissue expansion, and impaired strength and endurance despite normalization of joint swelling. RA muscle showed sustained myostatin (MSTN) elevation, Akt/mTOR suppression, impaired regeneration, senescence markers, and disrupted purinergic signaling characterized by reduced adenosine levels, diminished adenosine A2B receptor (A2BR) expression, and decreased AMP-activated protein kinase (AMPK) activation. Dipyridamole administered after remission of joint swelling restored muscle adenosine availability, reactivated A2BR–AMPK signaling, suppressed MSTN, stimulated insulin-like growth factor 1 receptor (IGF1R)-dependent anabolic pathways, reduced fibrosis, and improved muscle function and fiber composition.
Conclusion: RA induces persistent sarcopenia that remains after inflammation resolution. Post-remission dipyridamole reverses this phenotype in association with restoration of adenosine signaling, increased A2BR expression, AMPK activation, and enhanced anabolic pathways, highlighting purinergic modulation as a promising therapeutic strategy to improve muscle integrity and function in RA remission.
Related
- Temporal Neuroimmune Changes During Primary and Persistent Experimental Toxoplasmic Encephalitis
- In Vitro Modeling of Sarcopenia-Related Pathology and Exercise-Associated Adaptations: Integration with In Silico Approaches
- Convergent Early Dysregulation of Sarcopenia-Associated Genes in Skeletal Muscle During Aging and SOD1G93A ALS Models
- Persistent Epigenetic Reprogramming Is Associated With Contrasting Drought‐Response Strategies in Citrus Scion–Rootstock Systems
- Resistance training prevents the development of sarcopenia induced by chronic cholestatic liver disease
BibTeX
@article{marcobonilla2026persistent,
title = {{Persistent sarcopenia after flare remission in experimental RA responds to dipyridamole and is associated with restoration of adenosine and A2BR signaling}},
author = {Miguel Marco-Bonilla and Maria Fresnadillo and Fernando Huete-Toral and Gonzalo Carracedo and Gabriel Herrero-Beaumont and Raquel Largo and Aránzazu Mediero},
journal = {Frontiers in Pharmacology},
year = {2026},
month = oct,
doi = {10.3389/fphar.2026.1949677},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1949677/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Persistent sarcopenia after flare remission in experimental RA responds to dipyridamole and is associated with restoration of adenosine and A2BR signaling
AU - Miguel Marco-Bonilla
AU - Maria Fresnadillo
AU - Fernando Huete-Toral
AU - Gonzalo Carracedo
AU - Gabriel Herrero-Beaumont
AU - Raquel Largo
AU - Aránzazu Mediero
PY - 2026
DA - 2026/10/20
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1949677
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1949677/full
AB - Introduction: Rheumatoid arthritis (RA) is associated with systemic inflammation and sarcopenia, which often persist despite successful control of joint swelling and the mechanisms sustaining it remain unclear. Methods: Using the K/BxN serum-transfer model, we evaluated muscle structure, metabolism, and function after inflammatory remission. Dipyridamole was administered after remission of joint swelling to assess whether enhancement of adenosine and adenosine receptor signaling restore muscle homeostasis. Histological, molecular, metabolic, and functional analyses were performed. Results: RA mice exhibited persistent loss of muscle mass, fiber atrophy, fibrosis, white adipose tissue expansion, and impaired strength and endurance despite normalization of joint swelling. RA muscle showed sustained myostatin (MSTN) elevation, Akt/mTOR suppression, impaired regeneration, senescence markers, and disrupted purinergic signaling characterized by reduced adenosine levels, diminished adenosine A2B receptor (A2BR) expression, and decreased AMP-activated protein kinase (AMPK) activation. Dipyridamole administered after remission of joint swelling restored muscle adenosine availability, reactivated A2BR–AMPK signaling, suppressed MSTN, stimulated insulin-like growth factor 1 receptor (IGF1R)-dependent anabolic pathways, reduced fibrosis, and improved muscle function and fiber composition. Conclusion: RA induces persistent sarcopenia that remains after inflammation resolution. Post-remission dipyridamole reverses this phenotype in association with restoration of adenosine signaling, increased A2BR expression, AMPK activation, and enhanced anabolic pathways, highlighting purinergic modulation as a promising therapeutic strategy to improve muscle integrity and function in RA remission.
SN - 1663-9812
ER -