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

Although rheumatoid arthritis affects 1% of the global population, the role of rheumatoid cachexia, which occurs in up to a third of patients, is relatively neglected as research focus, despite its significant contribution to decreased quality of life in patients. A better understanding of the cellular and molecular processes involved in rheumatoid cachexia, as well as its potential treatment, is dependent on elucidation of the intricate interactions of the cells involved, such as myoblasts, fibroblasts and macrophages. Persistent RA-associated inflammation results in a relative depletion of the capacity for regeneration and repair in the satellite cell niche. The repair that does proceed is suboptimal due to dysregulated communication from the other cellular role players in this multi-cellular environment. This includes the incomplete switch in macrophage phenotype resulting in a lingering pro-inflammatory state within the tissues, as well as fibroblast-associated dysregulation of the dynamic control of the extracellular matrix. Additional to this endogenous dysregulation, some treatment strategies for RA may exacerbate muscle wasting and no multi-cell investigation has been done in this context. This review summarizes the most recent literature characterising clinical RA cachexia and links these features to the roles of and complex communication between multiple cellular contributors in the muscle niche, highlighting the importance of a targeted approach to therapeutic intervention.

High species homology potentiates quantitative inflammation profiling in zebrafish using immunofluorescence.

Due to substantial homology between the human and zebrafish genome and a high level of conservation of the innate immune system across species, zebrafish larvae have become an invaluable research tool for studying inflammation and modelling inflammatory disease. However, further microscopy techniques need to be developed for better profiling of inflammation and in particular, integrated cytokine responses to different stimuli - approaches are currently largely limited to assessment of changes in cytokine gene transcription and in vivo visualisation using transgenics, which is limited in terms of the number of cytokines that may be assessed at once. In this study, after confirming substantial homology of human vs zebrafish cytokine amino acid sequences, immunofluorescence staining using antibodies directed at human cytokines was performed. Inflammatory cytokine signalling responses to experimental tailfin transection was assessed over 24 h (1 hpi (hours post injury), 2 hpi, 4 hpi, 24 hpi) in zebrafish larvae, with experimental end point at 120 h post fertilization (hpf). When immunofluorescence results were compared to responses observed in rodent and human literature, it is clear that the cytokines follow a similar response, albeit with a condensed total time course. Notably, tumor necrosis factor-α and monocyte chemoattractant protein-1 increased and remained elevated over the 24-h period. In contrast, interleukin-1ß and interleukin-6 peaked at 4 hpi and 2 hpi respectively but had both returned to baseline levels by 24 hpi. Macrophage migration inhibitory factor was lowest at 1 hpi, potentially encouraging macrophage movement into the site of injury, followed by a sharp increase. This protocol provides valuable insight into inflammation over a time course and more so, provides an affordable and accessible method to comprehensively assess inflammation in zebrafish disease models.

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

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.