Background/Purpose: Persons with rheumatoid arthritis (RA) have poor cardiorespiratory fitness and are at increased risk for cardiometabolic co-morbidities. Endurance exercise training improves cardiorespiratory fitness in RA and lessens risk for cardiovascular disease and mortality in the general population; however, the pathways that contribute to the beneficial effects of exercise are largely unknown. In this study of RA participants completing a high-intensity interval training (HIIT) program, our goal was to identify relationships between improvements in cardiorespiratory fitness with changes in peripheral T cell and skeletal muscle mitochondrial metabolism.

Methods: Previously sedentary RA participants (n=12), who all satisfied 1987 ACR criteria, underwent phlebotomy and skeletal muscle biopsies before and after 10 weeks of HIIT. Available paired samples of peripheral blood mononuclear cells (n=6) and skeletal muscle (n=9) were used for primary analyses. Isolated peripheral CD4+ T cell mitochondrial respiration and glycolytic metabolism were assessed via Seahorse XF extracellular flux analyzer. Peripheral lymphocyte and CD4+ T cell subpopulations were measured by flow cytometry. Skeletal muscle mitochondrial metabolism was assessed via citrate synthase (CS) and carnitine acetyltransferase (CrAT) enzyme activity assays, and electron transport chain Western blot protein quantification. To inform mitochondrial metabolism analyses, targeted skeletal muscle and plasma metabolomic profiling (n=12) were performed. Relationships were assessed using Spearman’s correlations.

Results: Increases in RA cardiorespiratory fitness following HIIT were significantly associated with increases in RA peripheral CD4+ T cell basal and maximal respiration (rho=0.89, p=0.019 for both) and skeletal muscle CrAT activity (rho=0.70, p=0.036). Increases in CD4+ T cell mitochondrial respiration were significantly associated with increases in circulating naïve CD4+CCR7+CD45RA+ T cells (rho=0.89, p=0.019) and multiple skeletal muscle acylcarnitines. There was large interindividual variability in RA immune cell and skeletal muscle mitochondrial metabolism responses; however, skeletal muscle CrAT activity (mean increase=23.19%, SD=8.24%; p=0.035) significantly improved following HIIT.

Conclusion: In RA, exercise training-related increases in cardiorespiratory fitness associate with improvements in peripheral helper T cell and skeletal muscle oxidative metabolism, which are themselves related. Monitoring of cardiorespiratory fitness with individualized exercise prescription may be valuable in the management of chronic inflammation and cardiometabolic risk in RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/high-intensity-interval-training-increases-rheumatoid-arthritis-cardiorespiratory-fitness-in-association-with-improvements-in-cd4-t-cell-and-skeletal-muscle-mitochondrial-metabolism/