Evaluation of cytosolic DNA synthesis rates as a potential driver of musculoskeletal aging in the Hartley guinea pig

Abstract

Advancing age is the greatest risk factor for many chronic diseases and, by 2035, the number of U.S. citizens over the age of 65 will exceed the number under the age of 18 for the first time in history. Inflammaging, systemic aging associated low grade chronic inflammation, is a contributing factor to age-related chronic disease in multiple tissue types and organ systems, including the musculoskeletal system. Age-related musculoskeletal decline is characterized by diseases such as sarcopenia and osteoarthritis and has a strong correlation with an increase in all-cause mortality. While markers of inflammation are present in circulation, key drivers of inflammation that propagate age-related musculoskeletal decline are not well established. However, DNA that resides misplaced in the cytosol (cytoDNA) is a potent activator of the cGAS-STING pathway, an innate immune response that drives inflammation and disrupts cell function. While cytoDNA and the cGAS-STING pathway have been linked to increased inflammation in a host of tissues and disease states, very little evidence supports its role in skeletal muscle aging. Hartley guinea pigs (HGPs) are a translational, non-transgenic model of spontaneous musculoskeletal decline known to develop systemic inflammation and progressive age-related comorbidities characteristic of human aging. To begin establishing if cytoDNA contributes to age-related musculoskeletal decline, we assessed age-related differences in rates of newly synthesized cytoDNA in the tibialis anterior (TA), a locomotor muscle susceptible to age-related decline, from male and female 5- and 15-month-old (mo) HGPs. To assess this, we used stable isotope labeling with deuterium oxide, a sensitive approach for measuring rates of DNA synthesis in vivo. Although our primary findings showed that overall rates of cytoDNA synthesis did not increase with age or differ between sexes, we did identify a species of cytoDNA for which synthesis decreased with age, suggesting that the relationship between cytoDNA synthesis and aging is more complex than initially anticipated.