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

Brian J Andonian, Andrew Johannemann, Monica J Hubal, David M Pober, Alec Koss, William E Kraus, David B Bartlett, Kim M Huffman, Brian J Andonian, Andrew Johannemann, Monica J Hubal, David M Pober, Alec Koss, William E Kraus, David B Bartlett, Kim M Huffman

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.

Keywords: Cardiorespiratory fitness; Disease activity; Exercise training; Gene expression; Inflammation; Metabolism; Rheumatoid arthritis; Skeletal muscle.

Conflict of interest statement

Author DMP is an employee at Phastar Inc. (Cambridge, MA, USA). All other authors declare that they have no competing interests.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Top rheumatoid arthritis skeletal muscle gene associations with inflammatory disease activity. a Bar chart categorizing top rheumatoid arthritis (RA) skeletal muscle differentially expressed genes highly associated (Spearman’s rho p < 0.001) with RA disease activity score in 28 joints (DAS-28) by PANTHER gene ontology (GO) biological processes (bars represent total number genes per category; percent gene process hits/total listed next to bars). b Bar chart showing Reactome pathways overrepresented (>2 genes per pathway) within top RA skeletal muscle genes highly associated (p < 0.001) with disease activity. c Bar chart categorizing top baseline RA skeletal muscle differentially expressed genes highly associated (Spearman’s rho p < 0.001) with improvement in RA disease activity following high-intensity interval training (HIIT) by PANTHER GO biological processes (bars represent total number genes per category; percent gene process hits/total listed next to bars). d Bar chart showing Reactome pathways overrepresented (>2 genes per pathway) within top baseline RA skeletal muscle genes highly associated (p < 0.001) with improvement in disease activity following HIIT. *Represents pathway that reached significance at the calculated false discovery rate (p < 0.05)
Fig. 2
Fig. 2
Is altered skeletal muscle metabolism linked to fueling chronic inflammation? Figure summarizes skeletal muscle cellular metabolic pathways that may contribute to rheumatoid arthritis (RA) chronic inflammation based on differentially expressed RA muscle genes that are highly associated with disease activity score in 28 joints (DAS-28) (*) or improvements in DAS-28 following high-intensity interval training (HIIT) (#). Genes included in the pathways diagram are either highly associated (Spearman’s rho p < 0.001) or part of significantly associated ingenuity canonical pathways (p < 0.05). Genes whose expression significantly (p < 0.05) changes following HIIT are listed ($). Based on direction of positive (↑) or negative (↓) associations, genes whose function is to promote/upregulate (blue) or inhibit/downregulate (red) a specific pathway are highlighted. Bolded arrows represent proposed upregulated pathways. Dashed arrows represent proposed downregulated pathways. Green end-dotted arrows represent hypothesized pathways in which altered skeletal muscle metabolism may contribute to chronic immune-activation and inflammation in RA

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