Skeletal muscle dysregulation in rheumatoid arthritis: Metabolic and molecular markers in a rodent model and patients

Figures

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  Fig 1. Increased pain and paw swelling accompanied by low locomotor activity in the rat CIA model. Paw withdrawal thresholds (A) were reduced, and paw thickness increased (B) 18 days after collagen-induced arthritis in CIA rats (n = 9) compared to control (n = 9). Both horizontal (C) and vertical (D) activity, which were measured during the dark cycle before testing pain, decreased on the night of day 17 post immunisation in CIA group compared to control. Results represent mean±SEM. *p<0.05, **p<0.01, ***p<0.001, significantly different from control.

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  Fig 2. Indices of increased inflammation in the rat CIA model of RA. Plasma inflammatory cytokine IL-6 concentration (A) in the CIA group (n = 7) was greater than in control (n = 6) at the end of the study (day 18), but TNFα and IL-10 levels were similar to control. Histopathology (B), scale bar 200 μm, confirmed at the end of the study the development of arthritis in the tibiotalar joints of the CIA rats (n = 7) only, with increased cellularity, synovium lining thickness, and synovitis (C). TA- talus; TI- tibia; S- synovium. Results represent mean±SEM. **p<0.01, significantly different from control.

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  Fig 3. Muscle glycogen, intermediary metabolites and the protein: DNA ratio in the EDL muscle (n = 9 each group). Muscle glycogen content (A) was less and lactate (B) content greater in the EDL of CIA rats compared to control. In contrast, ATP, phosphocreatine (PCr) and creatine (Cr) content remained stable, indicating muscle viability in both groups (C). The alkaline-soluble protein: DNA ratio in CIA group tended to be lower than in control (D). Results represent mean±SEM. *p<0.05, **p<0.01, significantly different from control.

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  Fig 4. Expression of muscle mRNAs in the CIA model and patients with RA, relative to their corresponding control. Forty-six individual mRNAs in EDL muscle from CIA (n = 9) and control (n = 9) rats were quantified using TLDA cards (A). Eighteen of the most differentially regulated of these genes were also quantified in quadriceps muscle of patients with RA (n = 7) and expressed relative to the muscle from age-matched healthy control volunteers (n = 6; B). Results represent mean±SEM. *p<0.05, **p<0.01; significantly different from control.

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  Fig 5. Schematic of the prediction of metabolic events in muscle of CIA rats by Ingenuity Pathway Analysis. The outer ring reflects the most differentially regulated mRNAs in CIA rats compared to control rats and with the colour intensity associated with a p-value and reflecting greater (red) or less (green) expression relative to control. The centre of each ring reflects Ingenuity Pathway Analysis prediction of inhibition of carbohydrate and fatty acid metabolism (A) and activation of protein metabolism (B) in the CIA group based on the collective mRNA expression changes from control.