Exercise protects against cardiac and skeletal muscle dysfunction in a mouse model of inflammatory arthritis

Rheumatoid arthritis (RA) is a systemic inflammatory arthritis impacting primarily joints and cardiac and skeletal muscle. RA's distinct impact on cardiac and skeletal muscle tissue is suggested by studies showing that new RA pharmacologic agents strongly improve joint inflammation, but have little impact on RA-associated mortality, cardiovascular disease, and sarcopenia. Thus, the objective is to understand the distinct effects of RA on cardiac and skeletal muscle, and to therapeutically target these tissues through endurance-based exercise as a way to improve RA mortality and morbidity. We utilize the well-characterized RA mouse model, the K/BxN mouse, to investigate cardiac and skeletal muscle pathologies, including the use of wheel-running exercise to mitigate these pathologies. Strikingly, we found that K/BxN mice, like patients with RA, also exhibit both cardiac and skeletal muscle myopathies that were correlated with circulating IL-6 levels. Three months of wheel-running exercise significantly improved K/BxN joint swelling and reduced systemic IL-6 concentrations. Importantly, there were morphological, gene expression, and functional improvements in both the skeletal muscle and cardiac myopathies with exercise. The K/BxN mouse model of RA recapitulated important RA clinical comorbidities, including altered joint, cardiac and skeletal muscle function. These morphological, molecular, and functional alterations were mitigated with regular exercise, thus suggesting exercise as a potential therapeutic intervention to lessen disease activity in the joint and the peripheral tissues, including the heart and skeletal muscle.NEW & NOTEWORTHY RA, even when controlled, is associated with skeletal muscle weakness and greater risk of cardiovascular disease (CVD). Using exercise as a therapeutic against, the progression of RA is often avoided due to fear of worsening RA pathology. We introduce the K/BxN mouse as an RA model to study both myocardial and skeletal muscle dysfunction. We show that endurance exercise can improve joint, cardiac, and skeletal muscle function in K/BxN mice, suggesting exercise may be beneficial for patients with RA.