title: Advanced glycation end-products reduce collagen molecular sliding to affect collagen fibril damage mechanisms but not stiffness.
abstract: Advanced glycation end-products (AGE) contribute to age-related connective tissue damage and functional deficit. The documented association between AGE formation on collagens and the correlated progressive stiffening of tissues has widely been presumed causative, despite the lack of mechanistic understanding. The present study investigates precisely how AGEs affect mechanical function of the collagen fibril--the supramolecular functional load-bearing unit within most tissues. 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 (2.5 GPa) 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.
authors.affiliation: Department of Orthopedics, Balgrist University Hospital, University of Zurich, Zurich, Switzerland; Institute for Biomechanics, ETH Zurich, Zurich, Switzerland.
authors.forename: Gion
authors.initials: G
authors.lastname: Fessel
authors.affiliation: Department of Orthopedics, Balgrist University Hospital, University of Zurich, Zurich, Switzerland; Institute for Biomechanics, ETH Zurich, Zurich, Switzerland.
authors.forename: Yufei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute for Chemical and Bioengineering, ETH Zurich, Zurich, Switzerland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Diederich
authors.affiliation: Paul Scherrer Institute, Villigen, Switzerland.
authors.forename: Manuel
authors.initials: M
authors.lastname: Guizar-Sicairos
authors.affiliation: Institute for Biomechanics, ETH Zurich, Zurich, Switzerland; Faculty of Engineering and the Environment, University of Southampton, Southampton, United Kingdom.
authors.forename: Philipp
authors.initials: P
authors.lastname: Schneider
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: David R
authors.initials: DR
authors.lastname: Sell
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, Ohio, United States of America; Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, United States of America.
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Monnier
authors.affiliation: Department of Orthopedics, Balgrist University Hospital, University of Zurich, Zurich, Switzerland; Institute for Biomechanics, ETH Zurich, Zurich, Switzerland.
authors.forename: Jess G
authors.initials: JG
authors.lastname: Snedeker
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D003238:Connective Tissue / Q000378:metabolism / Q000473:pathology; D024022:Fibrillar Collagens / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D008954:Models, Biological; D051381:Rats; D013710:Tendons / Q000378:metabolism / Q000473:pathology
chemical_list: D024022:Fibrillar Collagens; D017127:Glycation End Products, Advanced