Post-remission muscle loss in rheumatoid arthritis improved by dipyridamole in mice

In mice with experimentally induced rheumatoid arthritis, muscle loss and impaired function persisted even after joint swelling had disappeared. Starting dipyridamole after this inflammatory remission improved much of the affected muscle mass, strength, endurance and tissue structure, an effect associated with increased muscle adenosine, adenosine A2B receptor signaling and activation of AMPK. The study identifies a persistent muscle impairment left by rheumatoid arthritis and suggests that restoring purinergic signaling may help recover muscle function after inflammation has subsided, although the findings have not yet been tested in patients.

Researchers used the K/BxN serum-transfer model, in which pooled serum from arthritic mice transfers arthritis-like disease to healthy recipient animals. Twelve-week-old male C57BL/6J mice were assigned to healthy controls, untreated arthritic controls or arthritic animals given dipyridamole. Arthritis developed after two serum injections, peaked around day 15 and resolved by day 28. Treatment began only after that remission point and continued until the animals were examined on day 45. The investigators assessed paw swelling, body and tissue weights, motor performance, muscle histology, nucleotide concentrations, gene expression and intracellular signaling. Body-weight recovery was defined in advance as the primary outcome, while the other measures were secondary or exploratory outcomes.

Untreated arthritic mice retained a marked muscle deficit after their joints recovered. Their body weight remained below that of healthy controls, while the gastrocnemius and tibialis anterior muscles weighed less. White adipose tissue remained enlarged, although brown adipose tissue returned to a control-like mass. Functional testing told a similar story. Activity, forelimb grip strength and two-limb hanging endurance were reduced through much of the study, while rotarod performance recovered late in the observation period. Dipyridamole did not restore every measurement immediately, but by week 6 it had returned ambulation, grip strength and hanging endurance to levels comparable with healthy animals and further improved rotarod performance. Body weight also increased after two weeks of treatment, although it did not fully reach the sham level during the experiment.

Tissue analysis showed that untreated arthritic mice had smaller muscle fibers, an excess of type II fibers compared with the type I predominance in controls, and increased collagen deposition consistent with fibrosis. Dipyridamole attenuated fiber atrophy, shifted fiber composition back toward type I and limited collagen accumulation to the sarcolemma. It also reduced the number of fibers containing intracellular immunoglobulin, which the researchers used as an indicator of myofiber necrosis. These tissue-level changes coincided with better performance, linking structural preservation with functional recovery. The findings show that muscle abnormalities were present after joint swelling had resolved; they do not establish reduced movement during active arthritis as the cause of those abnormalities.

Chemical analysis of gastrocnemius tissue revealed a metabolic signature that persisted despite remission. Compared with healthy controls, arthritic mice had significantly less adenosine and AMP but more ATP, producing a markedly depressed AMP-to-ATP ratio. Inosine did not differ among the groups, and adenosine diphosphate was lower in arthritic muscle but was not changed by treatment. Dipyridamole reversed the principal abnormalities: muscle adenosine and AMP concentrations recovered, and the AMP-to-ATP ratio returned to a level similar to that of controls. These changes were accompanied by increased expression of the adenosine A2B receptor, or A2BR, and greater phosphorylation of AMP-activated protein kinase, or AMPK. The observed benefits therefore coincided with restoration of adenosine-related signaling, although the experiment did not establish that A2BR was required for the treatment effect.

The molecular findings also indicate that the persistent weakness involved both catabolic and anabolic pathways. Untreated arthritic muscle retained elevated myostatin, a factor associated with inhibition of muscle growth, while the Akt/mTOR anabolic pathway was suppressed. Dipyridamole reduced myostatin expression, increased insulin-like growth factor 1 receptor expression and stimulated Akt/mTOR signaling. It also reduced Murf-1, a gene related to muscle degradation, although the other measured ubiquitin-proteasome marker, Atrogin-1, did not differ between groups. The senescence-associated marker p16 was elevated in arthritic muscle and fell with treatment, whereas p21 was unchanged. No differences were detected in Pax7, myogenin or myosin heavy-chain expression, although dipyridamole increased Myf5 and reduced the elevated MyoD seen in untreated arthritic muscle. The pattern was consistent with improved muscle maintenance and anabolic capacity, but it was not a wholesale correction of every molecular marker.

The results support the concept of a “sarcopenic imprint,” in which rheumatoid arthritis leaves lasting abnormalities in muscle after visible joint inflammation has resolved. In this model, that imprint included muscle atrophy, fibrosis, abnormal fiber composition, impaired regeneration, necrosis, altered energy metabolism and reduced strength and endurance. Some abnormalities were directly reversible with post-remission dipyridamole treatment, and the temporal sequence is important: the drug was introduced only after joint swelling had subsided. The work therefore goes beyond the observation that dipyridamole can influence muscle during active disease. It shows that starting treatment after remission can still improve a persistent muscle phenotype in this experimental system.

Several limitations prevent the findings from establishing a human treatment or proving that A2BR is indispensable. The investigators did not block or genetically delete A2BR, so the receptor’s causal role remains unproven; the relationship between receptor expression, AMPK activation and muscle recovery is associative. Dipyridamole is also not a selective A2BR modulator and changes several components of the purinergic system, making it difficult to assign the benefits to one receptor. Although the experiment began at the model’s established remission point, inflammatory mediators were not directly measured at the end of the current study, so residual inflammation cannot be completely excluded. There was no conventional disease-modifying antirheumatic drug or other anti-inflammatory comparator, and the cohort was small, included only male mice and was not replicated in female animals or people. Several individual observations were excluded after identification with the ROUT method at a Q of 1%; reanalysis including them did not change the overall interpretation.

The study nevertheless provides a mechanistic lead for a problem that can be overlooked when treatment is judged by joint symptoms alone. It shows that normalization of paw swelling in experimental rheumatoid arthritis does not necessarily mean that muscle homeostasis has recovered. Dipyridamole’s capacity to improve the post-remission phenotype while adenosine, A2BR and AMPK signaling were restored makes the adenosine pathway a plausible target for further investigation. Whether the same sequence occurs in people with rheumatoid arthritis remains unknown. Addressing that gap would require larger studies in both sexes, direct measurements of residual inflammation, receptor-specific experiments and clinical validation rather than extrapolation from this mouse model alone. The results should therefore be read as evidence for a possible post-remission muscle-targeting strategy, not as proof of a clinical benefit.

Subject of Research: Experimental post-remission muscle impairment in rheumatoid arthritis and dipyridamole treatment

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

Article References: Marco-Bonilla, M., Fresnadillo, M., Huete-Toral, F., Carracedo, G., Herrero-Beaumont, G., Largo, R., & Mediero, A. (2026). Persistent sarcopenia after flare remission in experimental RA responds to dipyridamole and is associated with restoration of adenosine and A2BR signaling. Frontiers in Pharmacology, 17, Article 1949677. https://doi.org/10.3389/fphar.2026.1949677

Image Credits: AI Generated

DOI: 10.3389/fphar.2026.1949677

Keywords: rheumatoid arthritis, sarcopenia, dipyridamole, adenosine, A2B receptor, skeletal muscle, AMPK, inflammation, mouse model, muscle fibrosis, Persistent, flare