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

IF 2.1 3区 医学 Q2 ORTHOPEDICS
Samuel J Mlawer, Felicia R Pinto, Katie J Sikes, Brianne K Connizzo
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Abstract

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.

随着年龄的增长,肌腱中葡萄糖和谷氨酰胺代谢的协调性丧失。
肌腱病是一种慢性退行性疾病,在老年人群中发病率增加,其特征是细胞外基质(ECM)完整性丧失。最近的研究已经清楚地表明,随着年龄的增长,ECM合成中的年龄相关缺陷以及代谢活动的一些变化。由于葡萄糖代谢对蛋白质合成至关重要,并且已知在衰老过程中会发生改变,因此我们试图研究与年龄相关的代谢变化是否与ECM重塑的变化有关。我们使用之前建立的屈肌腱外植体模型,将年轻和年老的肌腱外植体暴露于不同浓度的葡萄糖和谷氨酰胺中,观察代谢活性、基质组成、基质生物合成以及代谢和ECM基因表达的变化。我们假设葡萄糖和谷氨酰胺水平升高会导致年轻肌腱中ECM重塑增加以及各自通路的基因表达升高,而在老年肌腱中没有这种影响。有趣的是,我们发现谷氨酰胺加工受到葡萄糖水平的影响,关键谷氨酰胺加工途径的表达随着葡萄糖的增加而增加,但这种影响随着年龄的增长而消失。我们还观察到ECM重塑与葡萄糖和谷氨酰胺加工直接相关,葡萄糖和谷氨酰胺培养基浓度改变了糖胺聚糖和胶原合成。总之,我们的研究表明,葡萄糖和谷氨酰胺与细胞健康和ECM稳态有着复杂的联系,它们的代谢可能是组织维持中与年龄相关的缺陷的关键驱动因素之一。
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来源期刊
Journal of Orthopaedic Research®
Journal of Orthopaedic Research® 医学-整形外科
CiteScore
6.10
自引率
3.60%
发文量
261
审稿时长
3-6 weeks
期刊介绍: The Journal of Orthopaedic Research is the forum for the rapid publication of high quality reports of new information on the full spectrum of orthopaedic research, including life sciences, engineering, translational, and clinical studies.
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