Investigating the Mechanical Details of AGE Accumulation in Tissues

Advanced glycation end-products, AGEs, are a class of sugary metabolic waste produced in the normal operation of cellular biochemistry. Some types of AGE are short-lived and easily disposed of, while others are persistent and accumulate in tissues over time. These longer lived AGEs form cross-links in the extracellular matrix, the scaffolding of proteins that supports cells and determines the structural properties of tissue such as the strength of bone and cartilage or the elasticity of skin and blood vessels. Cross-linking has been shown to degrade tissue elasticity and strength, and is of particular interest as a contributing cause of blood vessel stiffening, one of the first steps leading to age-related cardiovascular disease.

In this paper researchers dig deeper into exactly how one particular type of AGE affects the mechanical properties of elastic tissue. They find, unexpectedly, that they cannot explain increasing tissue stiffness by examining the lowest level of extracellular matrix structure, where AGE cross-links form between collagen strands intended to slide alongside one another:

Collagen cross-linking by AGEs has been increasingly implicated as a central factor in the onset and progression of connective tissue disease. For the first time we report the physical effects of AGEs on collagen molecular and supramolecular deformations under load. We identify and describe altered damage mechanisms that could play a central role in connective tissue disease processes. Our data provide evidence that accumulation of AGEs dramatically affects collagen fibril failure behavior and stress relaxation. These functional parameters strongly reflect how collagen structures accommodate mechanical load and overload. Because the temporal and spatial dynamics of connective tissue damage and repair involve an intricate balance of mechanically driven catabolic and anabolic processes, even slight changes in collagen mechanics or patterns of damage accumulation may detrimentally affect tissue homeostasis. Such changes in extracellular matrix mechanics are likely to be exacerbated by resistance of AGE modified substrates to proteolytic enzymes that drive and regulate balanced matrix remodeling, or by chronic activation of inflammatory mediators that drive fibrosis.

We employed synchrotron small-angle X-ray scattering (SAXS) and carefully controlled mechanical testing after introducing AGEs in explants of rat-tail tendon using the metabolite methylglyoxal (MGO). Mass spectrometry and collagen fluorescence verified substantial formation of AGEs by the treatment. Associated mechanical changes of the tissue (increased stiffness and failure strength, decreased stress relaxation) were consistent with reports from the literature. SAXS analysis revealed clear changes in molecular deformation within MGO treated fibrils. Underlying the associated increase in tissue strength, we infer from the data that MGO modified collagen fibrils supported higher loads to failure by maintaining an intact quarter-staggered conformation to nearly twice the level of fibril strain in controls. This apparent increase in fibril failure resistance was characterized by reduced side-by-side sliding of collagen molecules within fibrils, reflecting lateral molecular interconnectivity by AGEs.

Surprisingly, no change in maximum fibril modulus accompanied the changes in fibril failure behavior, strongly contradicting the widespread assumption that tissue stiffening in ageing and diabetes is directly related to AGE increased fibril stiffness. We conclude that AGEs can alter physiologically relevant failure behavior of collagen fibrils, but that tissue level changes in stiffness likely occur at higher levels of tissue architecture.



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