Cookies help us deliver our services. By using our services, you agree to our use of cookies. More information

Horscroft 2014 Abstract MiP2014

From Bioblast
Substrate utilisation in the hypoxic heart: a glycolysis/glucose oxidation mismatch?

Link:

Horsecroft JA

Mitochondr Physiol Network 19.13 - MiP2014

Horscroft JA, Burgess SL, Murray AJ (2014)

Event: MiP2014

Hypoxia presents a physiological challenge to cardiac mitochondrial ATP generation [1]. Limiting atmospheric oxygen in both short-term chamber studies and longer term sojourns to altitude has been associated with decreased cardiac energetics in humans [2]. However, the metabolic mechanisms underlying these alterations are yet to be fully understood. Here, we set out to investigate the nature and timing of hypoxia-induced changes in cardiac substrate utilisation and electron transfer-pathway (ET-pathway) capacity, using high-resolution respirometry in permeabilized muscle fibres and enzyme activity assays.

Male Wistar rats were exposed to 10% environmental oxygen for either two or 14 days, with rats maintained in normoxia as controls. Despite a 12% loss in body mass (P<0.0001), 2 d hypoxia did not induce any metabolic changes. However, after 14 d hypoxia, tissue-mass specific OXPHOS capacity, driven by octanoyl carnitine (Oct+M) and pyruvate (P+M), dropped by 30% (P<0.05) and 21% (n.s.), respectively. The ratio of Oct to pyruvate-driven OXPHOS was 12% lower after 14 d hypoxia compared with controls (P<0.01), indicative of a switch in substrate preference. The loss of fatty acid oxidation capacity could not be explained by a loss of 3-hydroxyacyl-CoA dehydrogenase (HOAD) activity, as this was unaffected by hypoxia. Hexokinase activity, however, was augmented by 33%, following hypoxic exposure, when expressed relative to protein mass (P=0.02), and 39% when expressed relative to pyruvate-driven OXPHOS capacity (P=0.002), possibly indicating worsened coupling of glycolysis to glucose oxidation. In agreement with previous studies, 14 d hypoxia induced a 22% drop in Complex I-linked OXPHOS capacity (P<0.05). LEAK to OXPHOS ratio, a measure of mitochondrial uncoupling, was unaffected by hypoxia.

Paradigms of a hypoxia-induced metabolic substrate switch and the development of a diminished Complex I capacity are emerging, and these are supported by the present study. Although the molecular basis of the short-term loss in cardiac energetics is yet to be fully elucidated, the present data supports the hypothesis that the worsened energetic profile brought about by sustained hypoxia is propagated by a mismatch between glycolysis and glucose oxidation. The resulting proton production may have implications for mechanical function in the intact heart.


β€’ O2k-Network Lab: UK Cambridge Murray AJ


Labels: MiParea: Respiration 

Stress:Ischemia-reperfusion  Organism: Rat  Tissue;cell: Heart 


Coupling state: OXPHOS  Pathway: F, N  HRR: Oxygraph-2k  Event: B3, Oral  MiP2014 

Affiliation

Dept Physiol, Development & Neuroscience, Univ Cambridge, UK. - jah212@cam.ac.uk

References

  1. Heather LC, Cole MA, Tan JJ, Ambrose LJ, Pope S, Abd-Jamil AH (2012) Carter EE Metabolic adaptation to chronic hypoxia in cardiac mitochondria. Basic Res Cardiol 107: 268.
  2. Holloway CJ, Montgomery HE, Murray AJ, Cochlin LE, Codreana I, Hopwood N, Johnson AW, Rider OJ, Levett DZ, Tyler DJ, Francis JM, Neubauer S, Grocott MP, Clarke K (2011) Cardiac response to hypobaric hypoxia: persistent changes in cardiac mass, function and energy metabolism after a trek to Mt. Everest Base Camp. FASEB J 25: 792.