Rheumatoid arthritis (RA) is a model disease for studying premature aging. Despite revolutionary improvements in anti-inflammatory treatments over the past few decades, persons with RA continue to suffer from early aging-associated metabolic comorbidities, evidenced by an increased risk of sarcopenic obesity, insulin resistance, atherosclerosis and mortality. RA and aged immune cells have abnormal metabolic and mitochondrial function, which coincide with immune dysregulation. Skeletal muscle in both RA and aging is also marked by altered metabolism. In the proposed study, I will investigate whether dysfunction of mitochondria, the cellular metabolic ?engine,? connect RA peripheral helper T-cells, inflammatory macrophages and skeletal muscle abnormalities. My objectives for this pilot, feasibility study are twofold: 1) to determine whether RA peripheral T cell, macrophage and skeletal muscle mitochondrial function abnormalities are associated and 2) to determine the effects of exercise training on RA peripheral immune cell and skeletal muscle mitochondria. I hypothesize that 1) metabolic alterations in RA immune cells and skeletal muscle are interconnected, driven either by interorgan crosstalk or by master metabolic regulation; and 2) that interventions targeting global mitochondrial dysfunction will improve both cardiometabolic comorbidities and autoimmune disease in RA. As a first step to test my hypotheses in this pilot study, I will compare peripheral nave CD4+ T cell and inflammatory macrophage mitochondrial respiratory function to permeabilized muscle fiber mitochondrial respiratory function and near-infrared spectroscopy muscle oxidative capacity measurements in older persons (ages 55-85 years) with seropositive or erosive RA (n=10). I will also compare these immune cell and muscle mitochondrial function assessments in RA to age-, sex-, BMI-matched healthy controls (n=10). Additionally, using existing frozen samples, I will assess mitochondrial function responses to exercise training from 12 persons (age range 52-80) with RA that underwent a 10-week high intensity interval training exercise program. I will then use stored baseline and post-training immune cells and muscle tissue for mitochondrial function assessments in peripheral blood mononuclear cells and skeletal muscle. I expect that findings from this pilot study will provide a framework for my future research on interorgan metabolic regulation and mitochondrial adaptation to exercise training in both aging and RA. My results promise to increase scientific knowledge of the connections between two main ?pillars of aging?: inflammation and metabolism.
Immune cells and skeletal muscle are both dysfunctional and characterized by impaired metabolism in both rheumatoid arthritis and aging. Altered function of mitochondria, the powerhouses of metabolism in human cells, is one pathway that links rheumatoid arthritis to early aging and elevated risk of cardiometabolic disease and death. By learning how mitochondrial dysfunction is connected throughout the body, my research will help form the basis for new treatments targeting this prominent feature of aging and autoimmune disease.
