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Advanced glycation end-products reduce collagen molecular sliding to affect collagen fibril damage mechanisms but not stiffness

Advanced glycation end-products reduce collagen molecular sliding to affect collagen fibril damage mechanisms but not stiffness
Advanced glycation end-products reduce collagen molecular sliding to affect collagen fibril damage mechanisms but not stiffness
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.
1932-6203
1-12
Screen, Hazel R.C.
c39bc651-8aea-4c56-ba80-53bc0b308441
Fessel, Gion
16868591-da9a-46b4-b810-79eb203b070e
Li, Yufei
3e7ccf5f-fce5-485d-be85-a869ab956550
Diederich, Vincent
f17c1180-9ae0-4bcb-8c72-59f07c0f7d23
Guizar-Sicairos, Manuel
95872578-0eda-497e-9778-4147bf4b97d9
Schneider, Philipp
a810f925-4808-44e4-8a4a-a51586f9d7ad
Sell, David R.
5e5b64f4-f11d-4c95-a707-e1ca3c837fe4
Monnier, Vincent M.
fd012adb-78b3-4c1f-8d5d-bce612bcfd41
Snedeker, Jess G.
add85c93-a821-4282-8de5-4236752e9377
Screen, Hazel R.C.
c39bc651-8aea-4c56-ba80-53bc0b308441
Fessel, Gion
16868591-da9a-46b4-b810-79eb203b070e
Li, Yufei
3e7ccf5f-fce5-485d-be85-a869ab956550
Diederich, Vincent
f17c1180-9ae0-4bcb-8c72-59f07c0f7d23
Guizar-Sicairos, Manuel
95872578-0eda-497e-9778-4147bf4b97d9
Schneider, Philipp
a810f925-4808-44e4-8a4a-a51586f9d7ad
Sell, David R.
5e5b64f4-f11d-4c95-a707-e1ca3c837fe4
Monnier, Vincent M.
fd012adb-78b3-4c1f-8d5d-bce612bcfd41
Snedeker, Jess G.
add85c93-a821-4282-8de5-4236752e9377

Screen, Hazel R.C., Fessel, Gion, Li, Yufei, Diederich, Vincent, Guizar-Sicairos, Manuel, Schneider, Philipp, Sell, David R., Monnier, Vincent M. and Snedeker, Jess G. (2014) Advanced glycation end-products reduce collagen molecular sliding to affect collagen fibril damage mechanisms but not stiffness. PLoS ONE, 9 (11), 1-12. (doi:10.1371/journal.pone.0110948). (PMID:25364829)

Record type: Article

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.

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Accepted/In Press date: 8 August 2014
Published date: 3 November 2014
Organisations: Bioengineering Group

Identifiers

Local EPrints ID: 381913
URI: http://eprints.soton.ac.uk/id/eprint/381913
ISSN: 1932-6203
PURE UUID: 0ff57363-bb1a-484d-a14b-21fcfff8d045
ORCID for Philipp Schneider: ORCID iD orcid.org/0000-0001-7499-3576

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Date deposited: 01 Oct 2015 09:21
Last modified: 10 Dec 2019 01:34

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