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

Abstract

Rheumatoid arthritis (RA) T cells drive autoimmune features via metabolic reprogramming that reduces oxidative metabolism. Exercise training improves cardiorespiratory fitness (i.e., systemic oxidative metabolism) and thus may impact RA T cell oxidative metabolic function. In this pilot study of RA participants, we took advantage of heterogeneous responses to a high-intensity interval training (HIIT) exercise program to identify relationships between improvements in cardiorespiratory fitness with changes in peripheral T cell and skeletal muscle oxidative metabolism. In 12 previously sedentary persons with seropositive RA, maximal cardiopulmonary exercise tests, fasting blood, and vastus lateralis biopsies were obtained before and after 10 weeks of HIIT. Following HIIT, improvements in RA cardiorespiratory fitness were associated with changes in RA CD4 + T cell basal and maximal respiration and skeletal muscle carnitine acetyltransferase (CrAT) enzyme activity. Further, changes in CD4 + T cell respiration were associated with changes in naïve CD4 + CCR7 + CD45RA + T cells, muscle CrAT, and muscle medium-chain acylcarnitines and fat oxidation gene expression profiles. In summary, modulation of cardiorespiratory fitness and molecular markers of skeletal muscle oxidative metabolism during exercise training paralleled changes in T cell metabolism. Exercise training that improves RA cardiorespiratory fitness may therefore be valuable in managing pathologically related immune and muscle dysfunction.Trial registration: ClinicalTrials.gov, NCT02528344. Registered on 19 August 2015.

Conflict of interest statement

The authors declare no competing interests.

© 2022. The Author(s).

Figures

Figure 1

HIIT improves cardiorespiratory fitness in association with changes in RA CD4 + T cell oxidative function. Graphs show changes from before (Pre-HIIT) to after (Post-HIIT) high-intensity interval training (HIIT) in individual rheumatoid arthritis (RA) participant (subgroup n = 6) (A) cardiorespiratory fitness (relative VO2; ml/kg/min) and peripheral CD4 + T cell (B) basal, (C) ATP-linked, and (D) maximal respiration (oxygen consumption rate; ρmol O2/minute), and (E) basal oxygen consumption rate (OCR)/extracellular acidification rate (ECAR) ratio (OCR/ECAR ratio; ρmol/mpH). (F) Scatter plot depicts relationship between percent change in RA peripheral CD4 + T cell basal respiration (y-axis) and percent change in relative peak VO2 (x-axis) following HIIT. (G) Scatter plot depicts relationship between percent change in RA peripheral CD4 + T cell maximal respiration (y-axis) and percent change in relative peak VO2 (x-axis) following HIIT. (H) Scatter plot depicts relationship between percent change in RA CD4 + T cell OCR/ECAR ratio (y-axis) and percent change in relative peak VO2 (x-axis) following HIIT. *p < 0.05 for paired t-tests and Spearman correlations.

Figure 2

Changes in RA T cell oxidative metabolism following HIIT are associated with changes in naïve T cells. (A) Graphs show changes in rheumatoid arthritis (RA) peripheral CD3 + CD4 + helper T cells, CD3 + CD4- non-helper T cells, CD3-CD19 + B cells, CD3-CD56 + natural killer cells, and CD3 + CD56 + natural killer T cells following high-intensity interval training (HIIT) (subgroup n = 6; p > 0.05 for all pre-HIIT versus post-HIIT comparisons). (B) Graphs show changes in RA peripheral naïve CCR7 + CD45RA + , central memory CCR7 + CD45RA-, effector memory CCR7-CD45RA-, and terminally differentiated CCR7-CD45RA + CD4 + T cells following HIIT (p > 0.05 for all pre-HIIT versus post-HIIT comparisons). (C) Scatter plot depicts relationship between percent change in RA peripheral CD4 + T cell ATP linked respiration (y-axis) and percent change in peripheral naïve CD4 + T cells (x-axis) following HIIT. *p < 0.05 for paired t-tests and Spearman correlations.

Figure 3

HIIT increases RA skeletal muscle carnitine acetyltransferase enzyme activity in association with increased cardiorespiratory fitness and changes in CD4 + T cell oxidative function. Graphs show individual rheumatoid arthritis (RA) participant (subgroup n = 9) (A) cardiorespiratory fitness (relative VO2; ml/kg/min), skeletal muscle (B) carnitine acetyltransferase (mCrAT) and (C) citrate synthase enzyme activity (μmol/min/g) before (Pre-HIIT) and after (Post-HIIT) high-intensity interval training (HIIT). (D) Graphs show individual RA participant protein expression of mitochondrial complexes II, III, and V and electron transfer flavoprotein (ETF) Pre-HIIT and Post-HIIT. (E) Scatter plot depicts relationship between percent change in RA mCrAT enzyme activity (y-axis) and percent change and percent change in relative peak VO2 (ml/kg/min) (x-axis) following HIIT. (F) Scatter plot depicts relationship between percent change in RA mCrAT enzyme acitivity (y-axis) and percent change and percent change in peripheral CD4 + T cell ATP linked respiration (y-axis) following HIIT. *p < 0.05 for paired t-tests and Spearman correlations.

Figure 4

Changes in RA T cell respiration associate with changes in skeletal muscle acylcarnitine concentrations and increases in oxidative metabolism gene transcripts. (A) Heat map depicts correlations (Spearman’s rho) between percent change in rheumatoid arthritis (RA) peripheral CD4 + T cell respiration with plasma metabolites following high-intensity interval training (HIIT) (subgroup n = 6). (B) Heat map depicts correlations between percent change in RA peripheral CD4 + T cell respiration with skeletal muscle metabolites following HIIT (subgroup n = 6). (C) Heat map depicts correlations between percent change in RA peripheral CD4 + T cell respiration with skeletal muscle RNA with molecular relationships to carnitine acetyltransferase pathways (subgroup n = 6). *p < 0.05 (without multiple testing correction) for −0.8 ≤ rho ≤ 0.8. m Muscle, C Acylcarnitine.