Altered skeletal muscle metabolic pathways, age, systemic inflammation, and low cardiorespiratory fitness associate with improvements in disease activity following high-intensity interval training in persons with rheumatoid arthritis

Abstract

Background Exercise training, including high-intensity interval training (HIIT), improves rheumatoid arthritis (RA) inflammatory disease activity via unclear mechanisms. Because exercise requires skeletal muscle, skeletal muscle molecular pathways may contribute. The purpose of this study was to identify connections between skeletal muscle molecular pathways, RA disease activity, and RA disease activity improvements following HIIT. Methods RA disease activity assessments and vastus lateralis skeletal muscle biopsies were performed in two separate cohorts of persons with established, seropositive, and/or erosive RA. Body composition and objective physical activity assessments were also performed in both the cross-sectional cohort and the longitudinal group before and after 10 weeks of HIIT. Baseline clinical assessments and muscle RNA gene expression were correlated with RA disease activity score in 28 joints (DAS-28) and DAS-28 improvements following HIIT. Skeletal muscle gene expression changes with HIIT were evaluated using analysis of covariance and biological pathway analysis. Results RA inflammatory disease activity was associated with greater amounts of intramuscular adiposity and less vigorous aerobic exercise (both p < 0.05). HIIT-induced disease activity improvements were greatest in those with an older age, elevated erythrocyte sedimentation rate, low cardiorespiratory fitness, and a skeletal muscle molecular profile indicative of altered metabolic pathways (p < 0.05 for all). Specifically, disease activity improvements were linked to baseline expression of RA skeletal muscle genes with cellular functions to (1) increase amino acid catabolism and interconversion (GLDC, BCKDHB, AASS, PYCR, RPL15), (2) increase glycolytic lactate production (AGL, PDK2, LDHB, HIF1A), and (3) reduce oxidative metabolism via altered beta-oxidation (PXMP2, ACSS2), TCA cycle flux (OGDH, SUCLA2, MDH1B), and electron transport chain complex I function (NDUFV3). The muscle mitochondrial glycine cleavage system (GCS) was identified as critically involved in RA disease activity improvements given upregulation of multiple GCS genes at baseline, while GLDC was significantly downregulated following HIIT. Conclusion In the absence of physical activity, RA inflammatory disease activity is associated with transcriptional remodeling of skeletal muscle metabolism. Following exercise training, the greatest improvements in disease activity occur in older, more inflamed, and less fit persons with RA. These exercise training-induced immunomodulatory changes may occur via reprogramming muscle bioenergetic and amino acid/protein homeostatic pathways. Trial registration ClinicalTrials.gov, NCT02528344. Registered on 19 August 2015.

Rheumatoid arthritis T cell and muscle oxidative metabolism associate with exercise-induced changes in cardiorespiratory fitness

“…HIIT also improved skeletal muscle remodeling and innate immune cell inflammatory function in these patients 16 , 17 . We also observed that HIIT improved RA inflammatory disease activity in association with baseline transcriptomic remodeling of skeletal muscle amino acid and oxidative metabolism, providing evidence for a key role of skeletal muscle metabolism in reversing RA immune dysfunction 18 . While exercise training and increasing physical activity increase immune cell mitochondrial oxidative metabolism in healthy young and elderly individuals 19 – 23 , to our knowledge, this effect of exercise has not been previously studied in patients with RA.…”

“…In healthy persons, both immune cell and muscle oxidative metabolism improve with exercise training 19 – 23 ; these oxidative function gains suggest that in RA, exercise training could modify disease activity through metabolic reprogramming of immune cells and skeletal muscle. In this cohort of RA patients who completed 10 weeks of HIIT and improved inflammatory disease activity 18 , VO 2 peak improved in 11 of 12 participants. The subgroup of 6 RA participants for which T cell metabolism was assessed included one that had an unusually strong negative cardiorespiratory response to HIIT.…”

“…Here, we sought to expand our understanding of the effects of exercise training on RA beyond previous findings that HIIT improves RA cardiorespiratory fitness and disease activity. Using stored samples from the previously completed study 16 – 18 , we completed new analyses of changes in RA T cell metabolism and biomarkers of skeletal muscle metabolism following HIIT. Thus, the goal of this study was to take advantage of the heterogenous effects of exercise training on cardiorespiratory fitness to identify relationships between changes in RA systemic and organ-specific metabolism in the HIIT-trained cohort.…”

The Effects of High-Intensity Interval Training (HIIT) on Fall Risk Factors in Healthy Older Adults: A Systematic Review

“…HIIT has been prevalent among athletes for many years [14][15][16]. In recent years, HIIT protocols adjusted for non-athletic, healthy older adults, and adults with morbidities such as cardiac disease and rheumatoid arthritis have emerged [17][18][19][20][21]. This exercise approach has several advantages.…”

Three Months of Strength Training Changes the Gene Expression of Inflammation-Related Genes in PBMC of Older Women: A Randomized Controlled Trial

“…Physical exercise is now considered a powerful means to prevent and counter chronic diseases [32,33]. Many different exercise interventions have been proposed to counter CLIP in older adults but no consensus yet exists regarding the most effective exercise modality [34].…”