Work

Persistent sarcopenia after flare remission in experimental RA responds to dipyridamole and is associated with restoration of adenosine and A2BR signaling

Year: 2026

Type: article

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.

Source: Frontiers in Pharmacology

DOI: 10.3389/fphar.2026.1949677