Handzlik, Michal and Constantin-Teodosiu, Dumitru and Greenhaff, Paul L. and Cole, Mark (2018) Increasing cardiac pyruvate dehydrogenase flux during chronic hypoxia

The pattern of metabolic reprogramming in chronic hypoxia shares similarities with that following myocardial infarction or hypertrophy; however, the response of the chronically hypoxic heart to subsequent acute injury, and the role of metabolism is not well understood. Here, we determined the myocardial tolerance of the chronically hypoxic heart to subsequent acute injury, and hypothesised that activation of a key regulator of myocardial metabolism, the pyruvate dehydrogenase complex (PDC), could improve hypoxic tolerance. Mouse hearts, perfused in Langendorff mode, were exposed to 30 min of hypoxia, and lost 80% of pre-hypoxic function (P = 0.001), with only 51% recovery of pre-hypoxic function with 30 min of reoxygenation (P = 0.046). Activation of the PDC with infusion of 1 mM dichloroacetate (DCA) during hypoxia and reoxygenation did not alter function. Acute hypoxic tolerance was assessed in hearts of mice housed in hypoxia for 3 weeks. Chronic hypoxia reduced cardiac tolerance to subsequent acute Michal K. Handzlik is currently a Senior Fellow at the Mitochondria and Metabolism Centre at the University of Washington in Seattle, WA, USA. His research interests are in the field of cardiac energy metabolism. Following earning a BSc in Physiotherapy from the University School of Physical Education (AWF) in Wroclaw, Poland, he received his MSc in Exercise Physiology at Loughborough University, UK, and a PhD in Biomedical Sciences from the University of Nottingham, UK in the laboratory of Dr Mark A. Cole. C © 2018 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society DOI: 10.1113/JP275357 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. 2 M. K. Handzlik and others J Physiol 000.0 hypoxia, with recovery of function 22% of pre-acute hypoxic levels vs. 39% in normoxic control hearts (P = 0.012). DCA feeding in chronic hypoxia (per os, 70 mg kg−1 day−1) doubled cardiac acetylcarnitine content, and this fell following acute hypoxia. This acetylcarnitine use maintained cardiac ATP and glycogen content during acute hypoxia, with hypoxic tolerance normalised. In summary, chronic hypoxia renders the heart more susceptible to acute hypoxic injury, which can be improved by activation of the PDC and pooling of acetylcarnitine. This is the first study showing functional improvement of the chronically hypoxic heart with activation of the PDC, and offers therapeutic potential in cardiac disease with a hypoxic component. (Received 30 September 2017; accepted after revision 19 January 2018; first published online 31 January 2018) Corresponding author M. A. Cole: University of Nottingham Medical School, Queen’s Medical Centre, Nottingham NG7 2UH, UK. Email: mark.cole@nottingham.ac.uk