Temporal development of muscle atrophy in murine model of arthritis is related to disease severity

Abstract

BackgroundRheumatoid arthritis (RA) is an inflammatory autoimmune disease of unknown etiology, affecting mainly the joint but also other tissues. RA patients usually present weakness and muscle atrophy, nonarticular manifestations of the disease. Although causing great impact, the understanding of muscle atrophy, its development, and the mechanisms involved is still very limited. The objective of this study is to evaluate the development of muscle atrophy in skeletal muscle of a murine model of arthritis.MethodsThe experimental murine model of collagen-induced arthritis (CIA) was used. DBA/1J mice were randomly divided into three groups: control (CO, n = 25), sham arthritis (SA, n = 25), and arthritis (CIA, n = 28), analyzed in different time points: 25, 35, and 45 days after the induction of arthritis. The arthritis development was followed by clinical scores and hind paw edema three times a week. The spontaneous exploratory locomotion and weight were evaluated weekly. In all time points, serum was collected before the death of the animals for cytokine analysis, and myofiber cross-sectional areas (CSA) of gastrocnemius (GA) and tibialis anterior (TA) skeletal muscles were evaluated.ResultsThe clinical parameters of arthritis progressively increased in CIA in all experimental times, demonstrating the greatest difference from other groups at 45 days after induction (clinical score: CO, 00 ± 00; SA, 1.00 ± 0.14; CIA, 3.28 ± 0.41 p > 0.05). The CIA animals had lower weights during all the experimentation periods with a difference of 6 % from CO at 45 days (p > 0.05). CIA animals also demonstrated progressive decrease in distance walked, with a reduction of 54 % in 35 and 74 % at 45 days. Cytokine analysis identified significant increase in IL-6 serum levels in CIA than CO and SA in all experimental times. CSA of the myofiber of GA and TA was decreased 26 and 31 % (p > 0.05) in CIA in 45 days after the induction of disease, respectively. There was significant and inverse correlation between the disease clinical score and myofiber CSA in 45 days (GA: r = −0.71; p = 0.021).ConclusionOur results point to a progressive development of muscle wasting, with premature onset arthritis. These observations are relevant to understand the development of muscle loss, as well as for the design of future studies trying to understand the mechanisms involved in muscle wasting. As far as we are concerned, this is the first study to evaluate the relation between disease score and muscle atrophy in a model of arthritis.Electronic supplementary materialThe online version of this article (doi:10.1007/s13539-013-0102-1) contains supplementary material, which is available to authorized users.

Collagen‐induced arthritis as an animal model of rheumatoid cachexia

“…demonstrated a decrease in free locomotion and an inverse correlation between locomotion and muscle weight in CIA. Filippin et al . demonstrated that a progressive reduction in free locomotion was related to the development of arthritis, with a strong correlation between muscle loss and the severity of arthritis.…”

“…Fifty microliters of emulsion (CII + CFA) were injected intradermally at the base of the tail to induce arthritis; this was set as the day zero in this experiment. Eighteen days after the first injection, the animals received a reinforcement of CII emulsified with incomplete Freund's adjuvant (without M. tuberculosis ) in another site of the tail (booster injection) . During the procedures, mice were anaesthetized with isoflurane 10% (Abbott Laboratórios do Brasil Ltda., Brazil) and 90% of oxygen.…”

“…Eighteen days after the first injection, the animals received a reinforcement of CII emulsified with incomplete Freund's adjuvant (without M. tuberculosis) in another site of the tail (booster injection). 22 During the procedures, mice were anaesthetized with isoflurane 10% (Abbott Laboratórios do Brasil Ltda., Brazil) and 90% of oxygen. Healthy controls were manipulated and anaesthetized; however, no injection was made.…”

“…The collagen‐induced arthritis (CIA) animal model has many of the characteristics of RA, including clinical manifestations and histological and immunological features . Previous study of our group described the temporal development of muscle wasting in this animal model, but there are no data concerning other aspects of the cachexia observed in RA patients . However, it would be worth as an animal model to confirm if CIA mimic rheumatoid cachexia by showing similar changes observed in patients, as can be listed: decreased muscle mass (muscle atrophy), decreased muscle strength, increased fatigue, and abnormal serological biochemistry [increased inflammatory markers (TNFα, IL‐6), anaemia (Hb < 12 g·dL −1 ), low serum albumin (<3.2 g·dL −1 )].…”

“…21 Previous study of our group described the temporal development of muscle wasting in this animal model, but there are no data concerning other aspects of the cachexia observed in RA patients. 22 However, it would be worth as an animal model to confirm if CIA mimic rheumatoid cachexia by showing similar changes observed in patients, as can be listed: decreased muscle mass (muscle atrophy), decreased muscle strength, increased fatigue, and abnormal serological biochemistry [increased inflammatory markers (TNFα, IL-6), anaemia (Hb < 12 g·dL À1 ), low serum albumin (<3.2 g·dL À1 )]. Thus, the aim of this study was to assess the clinical characteristics of CIA to evaluate whether this animal model develops the clinical and functional features of rheumatoid cachexia.…”