Effects of Tofacitinib on Muscle Remodeling in Experimental Rheumatoid Sarcopenia

Sarcopenia is a frequent comorbidity of rheumatoid arthritis (RA). Clinical trials have shown that JAK inhibitors (JAKi) produce an asymptomatic increase in serum creatine kinase (CK) in RA, suggesting an impact on muscle. We evaluated the effect of JAKi in muscle remodeling in an experimental RA mo...

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Bibliographic Details
Published in:	International journal of molecular sciences 2023-09, Vol.24 (17), p.13181
Main Authors:	Bermejo-Álvarez, Ismael, Pérez-Baos, Sandra, Gratal, Paula, Medina, Juan Pablo, Largo, Raquel, Herrero-Beaumont, Gabriel, Mediero, Aránzazu
Format:	Article
Language:	eng
Subjects:	Albumin Analysis Arthritis Body weight C-reactive protein Creatine Creatine kinase Cytokines Gene expression Homeostasis JAK inhibitors Kinases Musculoskeletal system Proteins rheumatoid arthritis Rheumatoid factor Sarcopenia TOFA Tofacitinib
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Summary:	Sarcopenia is a frequent comorbidity of rheumatoid arthritis (RA). Clinical trials have shown that JAK inhibitors (JAKi) produce an asymptomatic increase in serum creatine kinase (CK) in RA, suggesting an impact on muscle. We evaluated the effect of JAKi in muscle remodeling in an experimental RA model. Antigen-induced arthritis (experimental RA, e-RA) was performed in 14 rabbits. Seven rabbits received tofacitinib (TOFA, orally 10 mg/kg/day). Animals were euthanized one day after the last ovalbumin injection, and muscles were prepared for histology, RT-PCR, and WB. C-reactive protein (CRP) and Myostatin (MSTN) serum concentration were determined by ELISA. Creatine and creatine kinase (CK) were analyzed. An increase in body weight as well as tibialis anterior cross-sectional area and diameter was observed in e-RA+TOFA vs. e-RA. e-RA decreased type II fibers and increased the myonuclei number, with all reverted by TOFA. TOFA did not modify CRP levels, neither did MSTN. TOFA significantly reduced IL-6, atrogin-1, and MuRF-1 compared with e-RA. e-RA+TOFA showed higher CK and lower creatine levels compared with e-RA. No differences in PAX-7 were found, while TOFA prevented the increase in MyoD1 in e-RA. Our model reflects the features of rheumatoid sarcopenia in RA. JAKi increased muscle mass through attenuating IL-6/JAK/STAT activation, decreasing atrogenes, and restoring muscle differentiation markers. These data together with an increase in CK support the role of CK as a valuable marker of muscle gain following JAKi treatment.
ISSN:	1422-0067 1661-6596 1422-0067