Impact of mitochondrial switching on contractile performance and substrate oxidation in the isolated working heart in rats with high or low genetically determined exercise capacity

Estelle Heyne (Jena)1, G. Reimann (Jena)1, J. Hoffmann (Jena)1, B. Mell (Toledo, OH)2, B. Joe (Toledo, OH)2, T. Doenst (Jena)1, M. Schwarzer (Jena)1

1Universitätsklinikum Jena Klinik für Herz- und Thoraxchirurgie Jena, Deutschland; 2The University of Toledo Department of Physiology and Pharmacology Toledo, OH, USA


Mitochondria are key determinants of cardiac function and metabolism. Variations of mitochondrial DNA (mtDNA) have been linked to differences in cardiac function as well as exercise capacity. Rats with high (HCR) or low (LCR) genetically determined exercise capacity display differences in their phenotype. While HCR are lean and considered as model of health, LCR display features of metabolic syndrome. HCR outperform LCR in terms of endurance running time and speed as well as longevity. Furthermore, these strains present with variations in mitochondria and substrate metabolism in skeletal muscle. Interestingly, LCR show a higher cardiac ischemia tolerance compared to HCR.

We now aimed to assess the role of mitochondrial switching (mtDNA differences) on cardiac function in adult HCR and LCR. We used the model of conplastic strains generated by breeding using maternal inheritance of mtDNA (HCR with mitochondria from LCR – HCR.LCRmt; LCR with mitochondria from HCR – LCR.HCRmt). Then we assessed cardiac contractile performance and substrate oxidation rates using radioactive tracers in the isolated working heart.

Cardiac weight was higher in LCR compared to HCR and did not change with mitochondrial switching. Unexpectedly, cardiac power in the isolated working heart was significantly lower in HCR compared to LCR (HCR vs LCR: 4.37 ± 0.43 vs 6.22 ± 0.39 mW), which was associated with a higher heart rate in HCR. Mitochondrial switching supported this observation - HCR with LCR mitochondria (HCR.LCRmt) had higher cardiac function compared to HCR, while LCR with HCR mitochondria (LCR.HCRmt) presented with significantly reduced cardiac power compared to LCR (LCR.HCRmt vs LCR: 35.5 ± 3.6 vs 46.2 ± 3.2 mW/gdry). Furthermore, HCR showed higher rates of fatty acid oxidation when related to cardiac power compared to LCR. At the same time glucose oxidation rates related to cardiac power were lower compared to LCR. Fatty acid oxidation rates did not appear to be affected by mitochondrial switching. Instead, glucose oxidation related to cardiac dry weight was lower in rats with mitochondria from LCR (LCR + HCR.LCRmt) compared to rats with mitochondria from HCR (HCR + LCR.HCRmt), highlighting a role of mtDNA in substrate metabolism.

These data suggest that mitochondrial switching affects contractile performance and substrate metabolism in rats with high or low genetically determined exercise capacity.

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