1. Treatment with tofacitinib attenuates muscle loss through myogenin activation in the collagen-induced arthritis.
- Author
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da Rosa TH, Bartikoski BJ, do Espírito Santo RC, Farinon M, de Souza Silva JM, Pedó RT, Gasparini ML, Karnopp T, Dos Santos LP, Chapacais G, di Domenico A, Loch S, and Xavier RM
- Subjects
- Animals, Male, Mice, Pyrroles therapeutic use, Pyrroles pharmacology, Muscular Atrophy drug therapy, Muscular Atrophy etiology, Piperidines therapeutic use, Piperidines pharmacology, Pyrimidines therapeutic use, Pyrimidines pharmacology, Arthritis, Experimental drug therapy, Muscle, Skeletal drug effects, Muscle, Skeletal pathology, Muscle, Skeletal metabolism, Mice, Inbred DBA, Myogenin metabolism
- Abstract
Background: Sarcopenia is a muscle disease characterized by reduction of muscle strength and muscle mass. In RA, 25.9 to 43.3% of the patients present sarcopenia. The loss of muscle mass observed in RA patients occurs either by activation of catabolic pathways or by inhibition of anabolic pathways. Despite having a list of drugs capable of treating RA inflammation, their effect on muscle is unclear. Our objective was to evaluate the tofacitinib effect on the muscle mass of collagen-induced arthritis (CIA) mice., Methods: CIA was induced in male DBA/1J mice by subcutaneous injection of Type 2 Collagen plus Freund Adjuvant. Animals were randomized into 3 groups: CIA + tofacitinib; CIA + vehicle; and healthy controls. Treatment was administered twice a day, between days 18 and 45 after induction. Clinical score, edema, and body weight were evaluated during the experimental period. After euthanasia, tibiotarsal joints were collected for assessment of disease histopathological score, and tibialis anterior (TA) and gastrocnemius (GA) muscles were weighed to assess muscle mass. Muscle atrophy was evaluated by measurement of TA myofiber cross-sectional area (CSA). Protein expression was evaluated by western blot using GA homogenates. Serum inflammatory markers were evaluated by ELISA. Statistical analysis included ANOVA followed by Tukey's or with Kruskal-Wallis. The statistical difference was assumed for p < 0.05., Results: Tofacitinib treatment decreased arthritis severity by reducing clinical score, and hind paw edema in comparison with the vehicle group. Tofacitinib showed weight gain, higher TA and GA weights, and increased CSA compared to the vehicle group. On day 45, Tofacitinib presented increased muscle strength compared to the vehicle group, however, no difference was found in muscle fatigue. Pax7 expression was unchanged, while MyoD expression showed an increasing trend, and myogenin expression was significantly increased in Tofacitinib compared to vehicle and control groups. The treatment didn't modify Murf-1 expression. Tofacitinib mice showed decreased serum levels of TNF and increased IL-6 serum levels., Conclusion: Tofacitinib attenuated muscle loss in arthritic mice, increased muscle weight and muscle CSA. Activation of satellite cell regeneration, based on the increased expression of myogenin, is a potential mechanism involved in tofacitinib action against muscle loss., Competing Interests: Declarations Ethical approval This study was approved by the Research Ethics Committee of the Hospital de Clínicas de Porto Alegre (protocol number 18-0302). Patient and public involvement Not applicable. Conflict of interest Thales Hein da Rosa, Bárbara Bartikoski, Rafaela Cavalheiro do Espírito Santo, Mirian Farinon, Jordana Miranda de Souza Silva, Renata Ternus Pedo, Maria Luísa Gasparini, Thaís Karnopp, Leonardo Santos, Gustavo Chapacais, Andressa Di Domenico, Sofia Loch: None declared, Ricardo Xavier Grant/research support from Pfizer Grant 60289911., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
- Published
- 2024
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