Thales Hein da Rosa, Bárbara Jonson Bartikoski, Rafaela Cavalheiro do Espírito Santo, Mirian Farinon, Jordana Miranda de Souza Silva, Renata Ternus Pedó, Maria Luísa Gasparini, Thais Karnopp, Leonardo Peterson Dos Santos, Gustavo Chapacais, Andressa di Domenico, Sofia Loch, Ricardo Machado Xavier
{"title":"在胶原蛋白诱导的关节炎中,托法替尼能通过激活肌原蛋白减轻肌肉损失。","authors":"Thales Hein da Rosa, Bárbara Jonson Bartikoski, Rafaela Cavalheiro do Espírito Santo, Mirian Farinon, Jordana Miranda de Souza Silva, Renata Ternus Pedó, Maria Luísa Gasparini, Thais Karnopp, Leonardo Peterson Dos Santos, Gustavo Chapacais, Andressa di Domenico, Sofia Loch, Ricardo Machado Xavier","doi":"10.1186/s42358-024-00416-5","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":48634,"journal":{"name":"Advances in Rheumatology","volume":"64 1","pages":"85"},"PeriodicalIF":2.0000,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Treatment with tofacitinib attenuates muscle loss through myogenin activation in the collagen-induced arthritis.\",\"authors\":\"Thales Hein da Rosa, Bárbara Jonson Bartikoski, Rafaela Cavalheiro do Espírito Santo, Mirian Farinon, Jordana Miranda de Souza Silva, Renata Ternus Pedó, Maria Luísa Gasparini, Thais Karnopp, Leonardo Peterson Dos Santos, Gustavo Chapacais, Andressa di Domenico, Sofia Loch, Ricardo Machado Xavier\",\"doi\":\"10.1186/s42358-024-00416-5\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusion: </strong>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.</p>\",\"PeriodicalId\":48634,\"journal\":{\"name\":\"Advances in Rheumatology\",\"volume\":\"64 1\",\"pages\":\"85\"},\"PeriodicalIF\":2.0000,\"publicationDate\":\"2024-11-13\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Advances in Rheumatology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s42358-024-00416-5\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"RHEUMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Advances in Rheumatology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s42358-024-00416-5","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"RHEUMATOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
背景:肌肉疏松症是一种以肌肉力量和肌肉质量下降为特征的肌肉疾病。在 RA 患者中,25.9%-43.3% 的患者出现肌肉疏松症。在 RA 患者身上观察到的肌肉质量下降是通过激活分解代谢途径或抑制合成代谢途径造成的。尽管有一系列药物可以治疗 RA 炎症,但它们对肌肉的影响尚不明确。我们的目的是评估托法替尼对胶原诱导的关节炎(CIA)小鼠肌肉质量的影响:方法:通过皮下注射2型胶原蛋白加弗罗因德佐剂诱导雄性DBA/1J小鼠患CIA。动物被随机分为 3 组:CIA+托法替尼组;CIA+药物组;健康对照组。诱导后第 18 天至第 45 天期间,每天治疗两次。在实验期间对临床评分、水肿和体重进行评估。安乐死后,收集胫跗关节以评估疾病组织病理学评分,称重胫骨前肌(TA)和腓肠肌(GA)以评估肌肉质量。通过测量TA肌纤维横截面积(CSA)评估肌肉萎缩情况。使用GA匀浆通过Western印迹评估蛋白质表达。血清炎症标记物通过 ELISA 进行评估。统计分析包括方差分析(ANOVA)、Tukey's 或 Kruskal-Wallis。统计差异假定为 p 结果:与载体组相比,托法替尼通过降低临床评分和后爪水肿减轻了关节炎的严重程度。与载体组相比,托法替尼显示体重增加,TA和GA重量增加,CSA增加。在第 45 天,与载体组相比,托法替尼增加了肌肉力量,但在肌肉疲劳方面没有发现差异。与载体组和对照组相比,托法替尼组的Pax7表达没有变化,而MyoD表达呈上升趋势,肌原蛋白表达显著增加。治疗没有改变 Murf-1 的表达。托法替尼小鼠血清中TNF水平降低,IL-6水平升高:结论:托法替尼减轻了关节炎小鼠的肌肉损失,增加了肌肉重量和肌肉CSA。基于myogenin表达的增加,激活卫星细胞再生是托法替尼防治肌肉损失的潜在机制。
Treatment with tofacitinib attenuates muscle loss through myogenin activation in the collagen-induced arthritis.
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.
期刊介绍:
Formerly named Revista Brasileira de Reumatologia, the journal is celebrating its 60th year of publication.
Advances in Rheumatology is an international, open access journal publishing pre-clinical, translational and clinical studies on all aspects of paediatric and adult rheumatic diseases, including degenerative, inflammatory and autoimmune conditions. The journal is the official publication of the Brazilian Society of Rheumatology and welcomes original research (including systematic reviews and meta-analyses), literature reviews, guidelines and letters arising from published material.