Fleming T.H.(1), Theilen T.-M. (1), Masania J. (6), Wunderle M. (1), Karimi J. (1,7), Vittas S. (1), Bernauer R. (1), Bierhaus A. (1), Rabbani N. (6), Thornalley P.J. (6), Kroll J. (5), Tyedmers J. (2), Nawrotzki R. (3), Herzig S. (4), Brownlee M. (8), Nawroth P.P. (1)
(1) Department of Medicine I and Clinical Chemistry, University of Heidelberg, (2) ZMBH, (3) Lehrstuhl II Medizinische Zellbiologie and (4) Joint Research Division, Molecular Metabolic Control, German Cancer Research Center DKFZ, Network Aging Research, ZMBH, University Hospital Heidelberg, Heidelberg, and (5) Centre for Biomedicine and Medical Technology Mannheim, University of Heidelberg, Mannheim, Germany; (6) Warwick Medical School, Clinical Sciences Research Institute, University Warwick, University Hospital, Coventry, UK; (7) Department of Clinical Biochemistry, Hamadan University of Medical Science, Hamadan, Iran; (8) Albert Einstein College of Medicine, Bronx, N.Y., USA.
Methylglyoxal (MG), the major dicarbonyl substrate of the enzyme glyoxalase 1 (GLO1), is a reactive metabolite formed via glycolytic flux. Decreased GLO1 activity in situ has been shown to result in an accumulation of MG and increased formation of advanced glycation endproducts, both of which can accumulate during physiological aging and at an accelerated rate in diabetes and other chronic degenerative diseases. To determine the physiological consequences which result from elevated MG levels and the role of MG and GLO1 in aging, wound healing in young (≤12 weeks) and old (≥52 weeks) wild-type mice was studied. Old mice were found to have a significantly slower rate of wound healing compared to young mice (74.9 ± 2.2 vs. 55.4 ± 1.5% wound closure at day 6; 26% decrease; p < 0.0001). This was associated with decreases in GLO1 transcription, expression and activity. The importance of GLO1 was confirmed in mice by inhibition of GLO1. Direct application of MG to the wounds of young mice, decreased wound healing by 24% compared to untreated mice, whereas application of BSA modified minimally by MG had no effect. Treatment of either young or old mice with aminoguanidine, a scavenger of free MG, significantly increased wound closure by 16% (66.8 ± 1.6 vs. 77.2 ± 3.1%; p < 0.05) and 64% (40.4 ± 7.9 vs. 66.4 ± 5.2%; p < 0.05), respectively, by day 6. As a result of the aminoguanidine treatment, the overall rate of wound healing in the old mice was restored to the level observed in the young mice. These findings were confirmed in vitro, as MG reduced migration and proliferation of fibroblasts derived from young and old, wild-type mice. The data demonstrate that the balance between MG and age-dependent GLO1 downregulation contributes to delayed wound healing in old mice.
Event date: 22/06/2013
Publication date: 25/05/2015