Redox Status and Muscle Pathology in Rheumatoid Arthritis: Insights from Various Rat Hindlimb Muscles

Abstract

Due to atrophy, muscle weakness is a common occurrence in rheumatoid arthritis (RA). The majority of human studies are conducted on the vastus lateralis muscle—a muscle with mixed fiber type—but little comparative data between multiple muscles in either rodent or human models are available. The current study therefore assessed both muscle ultrastructure and selected redox indicators across various muscles in a model of collagen-induced rheumatoid arthritis in female Sprague-Dawley rats. Only three muscles, the gastrocnemius, extensor digitorum longus (EDL), and soleus, had lower muscle mass (38%, 27%, and 25% loss of muscle mass, respectively; all at least P<0.01), while the vastus lateralis muscle mass was increased by 35% (P<0.01) in RA animals when compared to non-RA controls. However, all four muscles exhibited signs of deterioration indicative of rheumatoid cachexia. Cross-sectional area was similarly reduced in gastrocnemius, EDL, and soleus (60%, 58%, and 64%, respectively; all P<0.001), but vastus lateralis (22% smaller, P<0.05) was less affected, while collagen deposition was significantly increased in muscles. This pathology was associated with significant increases in tissue levels of reactive oxygen species (ROS) in all muscles except the vastus lateralis, while only the gastrocnemius had significantly increased levels of lipid peroxidation (TBARS) and antioxidant activity (FRAP). Current data illustrates the differential responses of different skeletal muscles of the hindlimb to a chronic inflammatory challenge both in terms of redox changes and resistance to cachexia.

Rheumatoid cachexia: the underappreciated role of myoblast, macrophage and fibroblast interplay in the skeletal muscle niche

“…In contrast, no difference in muscle weight and force production deficits between soleus and EDL muscles were reported in mice, suggesting that changes in gastrocnemius and EDL muscles might differ [37]. However, a recent study done by our group assessing the gastrocnemius, soleus and EDL muscles in rats, demonstrated a severe (≈60%) loss of muscle mass, but with similar severity in terms of reduction in CSA, left shift of fibre size distribution and histological evidence of fibre degradation [38], supporting the argument against muscle fibre type as major role player. Interestingly, atrophy was less pronounced in the vastus lateralis muscle, which suggests that other factors, such as body posture, distance of muscle from affected joints, or even muscle-specific differences in redox profile-which was detailed in this study [34]-may contribute relatively more to final outcome than fibre type itself.…”

“…3 Representative images suggesting the presence of different cell types in healthy versus rheumatoid arthritis skeletal muscle. Fluorescent images from a RA rodent model (study execution described in Oyenihi et al, 2019 [38]; staining method described in Additional file 1) indicate clear cachexia and increased fibrosis between muscle fibres. Black and white images indicative of the authors prediction of greater presence of macrophages (M1 and M2b) and fibroblasts in RA…”

“…In addition, both CCL3 (macrophage inflammatory protein 1α) and CCL2 (monocyte chemoattractant protein-1) have been highlighted as promotors of fibrosis through their chemotactic properties [81]. To add to this, fibroblasts were shown to have the capacity to promote arthritis through the production of GM-CSF, which enhances the survival of neutrophils and macrophages [87], thus further strengthening the inflammatory response in a vicious cycle, much like the self-propagating oxidative damage-inflammation cycle that also comes into play in chronic diseases such as RA [38]. Disturbance in the balance between classically activated (M1) and alternative (M2) macrophages therefore leads to excessive TGF-β production, resulting in excessive activation of fibroblasts and inhibited apoptosis of FAPs, resulting in excessive ECM production and fibrosis [56,80].…”

Prophylactic Application of Lavandula Angustifolia Mill. Oil and Its Active Component Linalyl Acetate Alleviate Comorbidity and Exacerbation Risk in Rats With Collagen-Induced Arthritis Accompanied by Chronic Nicotine-Induced Hypertension.

“…background area was subtracted from connective tissue and total tissue, then followed the formula: percentage of brosis = connective tissue/ connective tissue + total tissue x100 [25].…”

The therapeutic effects of edaravone on collagen‐induced arthritis in rats

“…To clarify the therapeutic effect of edaravone on arthritis, a total of 45 male rats were used and divided into three groups: normal control (NC), CIA model and treatment groups. The therapy CIA groups received one of three intraperitoneal injection doses (3,6, and 9 mL/kg, twice per day) of edaravone for 2, 4, and 6 weeks, respectively.…”