Coordination of Glucose and Glutamine Metabolism in Tendon Is Lost in Aging

Tendinopathy is a chronic, degenerative disease that has increased prevalence in aged populations, and is characterized by a loss in extracellular matrix (ECM) integrity. Recent work has clearly demonstrated age-related deficits in ECM synthesis with aging, as well as some changes to metabolic activity. Since glucose metabolism is critical to protein synthesis and known to be altered in aging, we sought to investigate if age-related changes in metabolism are linked to changes in ECM remodeling. We used our previously developed flexor tendon explant model to expose young and aged tendon explants to various concentrations of glucose and glutamine supplementation and observe changes in metabolic activity, matrix composition, matrix biosynthesis, and expression of metabolic and ECM genes. We hypothesized that elevated levels of glucose and glutamine would lead to increased ECM remodeling as well as elevated gene expression of their respective pathways in young tendons, with no such effect in aged tendons. Interestingly, we found that glutamine processing is affected by glucose levels with increased expression of key glutamine processing pathways with increased glucose, but this effect was lost with aging. We also observed that ECM remodeling is directly related to both glucose and glutamine processing with altered glycosaminoglycan and collagen synthesis with glucose and glutamine media concentration. Overall, our work reveals that glucose and glutamine are intricately linked for both tenocyte health and ECM homeostasis and that their metabolism could be one of the key drivers of age-related deficiencies in tissue maintenance.