Skeletal Muscle Metabolic Gene Profile Associates With Rheumatoid Arthritis Improvements Following High Intensity Interval Training

Abstract

Rheumatoid arthritis (RA) is a systemic inflammatory disease characterized by exercise intolerance and increased risk for cardiometabolic disease. High intensity interval training (HIIT) improves both inflammation and cardiorespiratory fitness (CRF) in RA, however the mechanisms underpinning these therapeutic benefits are unclear. PURPOSE: To identify baseline skeletal muscle pathways linking HIIT with improvements in RA inflammatory disease activity and CRF. METHODS: Participants with RA (n=13; mean age=63.9±7.2) underwent RA disease activity (DAS), physiologic, and biologic assessments pre- and post-10 weeks of supervised HIIT. Cardiopulmonary exercise testing measured CRF as rVO2 peak (mL/kg/min). Skeletal muscle RNA was isolated from vastus lateralis biopsies. Illumina Human HT-12v4 Expression BeadChips and Ingenuity Pathway Analysis were used for quantitative whole genome RNA analyses. Differential Spearman correlations (p<0.05) assessed associations for baseline gene expression with ΔDAS and ΔCRF (post - pre). RESULTS: HIIT improved RA DAS (+23.8%; p<0.001) and CRF (+8.2%; p<0.001). ΔDAS was strongly correlated with baseline muscle expression of 46 genes (0.80< r<-0.80; *p<0.001); including genes encoding proteins involved in substrate energy metabolism (n=9; LIAS, NDUFV3, GLDC, AGL, BCKDHB, PDK2, LDHB, ACSS2, PANK2) and inflammatory pathways (n=4; FCRL6, TNFRSF19, CMTM4, NKG7). In contrast, ΔCRF was strongly correlated with baseline expression of 16 genes; only 1 (NDUFB4) involved in cellular metabolism and 0 in inflammation. Novel network analysis revealed muscle upregulation of NF-kB and MAPK/JNK pathways associated with greater improvements in DAS. CONCLUSIONS: HIIT-mediated improvements in RA disease activity associate strongly with baseline alterations in skeletal muscle metabolic and inflammatory pathways. Thus, exercise training may improve RA inflammation via coordinated regulation of muscle and immune cell energy metabolism.