Advanced Glycation End-Products Suppress Mitochondrial Function and Proliferative Capacity of Achilles Tendon-Derived Fibroblasts

Shivam H Patel,Jonathan H Shannahan,Arman Sabbaghi,Chad C Carroll,Shannon K Saw,Shihuan Kuang,Jason R Cannon,Rachel Foguth,Feng Yue

doi:10.1038/s41598-019-49062-8

Abstract

Debilitating cases of tendon pain and degeneration affect the majority of diabetic individuals. The high rate of tendon degeneration persists even when glucose levels are well controlled, suggesting that other mechanisms may drive tendon degeneration in diabetic patients. The purpose of this study was to investigate the impact of advanced glycation end-products on tendon fibroblasts to further our mechanistic understanding of the development and progression of diabetic tendinopathy. We proposed that advanced glycation end-products would induce limitations to mitochondrial function and proliferative capacity in tendon-derived fibroblasts, restricting their ability to maintain biosynthesis of tendon extracellular matrix. Using an in-vitro cell culture system, rat Achilles tendon fibroblasts were treated with glycolaldehyde-derived advanced glycation end-products (0, 50, 100, and 200 μg/ml) for 48 hours in normal glucose (5.5 mM) and high glucose (25 mM) conditions. We demonstrate that tendon fibroblasts treated with advanced glycation end-products display reduced ATP production, electron transport efficiency, and proliferative capacity. These impairments were coupled with alterations in mitochondrial DNA content and expression of genes associated with extracellular matrix remodeling, mitochondrial energy metabolism, and apoptosis. Our findings suggest that advanced glycation end-products disrupt tendon fibroblast homeostasis and may be involved in the development and progression of diabetic tendinopathy.

Highlights

Advanced glycation end-product (AGE) formation is a non-enzymatic process in which free amine terminals are subjected to covalent modification by reactive glucose or other carbonyl containing molecules
We propose that AGEs contribute to the diabetic tendon phenotype by activating cellular pathways that limit mitochondrial function, thereby interfering with the capacity of tendon fibroblasts to maintain biosynthesis of tendon extracellular matrix (ECM)
We hypothesized that AGEs and high glucose medium would reduce mitochondrial DNA content and further contribute to limitations imposed to energy producing pathways in tendon fibroblasts

Summary

Introduction

Advanced glycation end-product (AGE) formation is a non-enzymatic process in which free amine terminals are subjected to covalent modification by reactive glucose or other carbonyl containing molecules. Www.nature.com/scientificreports tendon of mice[14] It is not known, what role circulating AGEs play in the development and progression of diabetic tendinopathy. In non-tendon models, AGEs have been shown to activate RAGE-mediated cellular pathways leading to impairments in mitochondrial function and apoptosis[15,16,17,18]. We propose that AGEs contribute to the diabetic tendon phenotype by activating cellular pathways that limit mitochondrial function, thereby interfering with the capacity of tendon fibroblasts to maintain biosynthesis of tendon ECM. We hypothesized that AGEs and high glucose medium would reduce mitochondrial DNA (mtDNA) content and further contribute to limitations imposed to energy producing pathways in tendon fibroblasts. This study provides new functional and descriptive perspective of the AGE insult on tendon fibroblast homeostasis

Objectives

Methods

Results

Conclusion