Abstract
Background – The heart adapts in response to stress by inducing adaptive remodelling pathways leading to cardiac hypertrophy, however this is not sustained and with continued stress, maladaptive remodelling pathways ensue, impairing cell viability and contractile function leading to heart failure. An emerging concept is that cardiac hypertrophy is paralleled by changes in cardiomyocyte metabolism, which may themselves drive cardiac hypertrophy. The proto-oncogene c-Myc is a key regulator of cancer metabolism that promotes anabolic pathways driving tumorigenesis. Interestingly, c-Myc overexpression in the heart causes hypertrophy but how this is accomplished remains unclear.Objective – Define the functional role of c-Myc during remodelling of the adult heart with a focus on the relationship to intermediary glucose metabolism pathways that support anabolic growth in response to different types of hypertrophic stress stimuli.
Methods – Cardiac-specific c-Myc knock-out (c-Myc KO) mice were generated and subjected to different types of stress stimuli. Pathological stress was induced by abdominal aortic banding (AAB) or transverse aortic constriction (TAC) and compared to sham surgery. Physiological stress was induced by voluntary wheel running (VWR) exercise and compared with sedentary controls. Metabolic pathway activity was comprehensively assessed by optimising a stable isotope resolved metabolomics method, using stable isotope labelled glucose (13C6 glucose) in ex-vivo Langendorff perfused hearts of floxed control and cs-c-Myc KO mice.
Results – The c-Myc KO mice appear phenotypically normal and do not exhibit any changes in cardiac structure or function at baseline. When subjected to chronic pressure overload, c-Myc KO mice show a similar decline in cardiac function and a similar extent of cardiac hypertrophy as their floxed littermates. After chronic pressure overload, there is a significant decrease in 13C label incorporation into TCA metabolites and its related amino acids in the cs-c-Myc KO mice. In parallel, metabolites related to the hexosamine biosynthesis pathway show an increased 13C label incorporation after pressure overload in the floxed mice which is attenuated in the c-Myc KO mice. When subjected to regular exercise, c-Myc KO mice develop cardiac hypertrophy to the same extent as the floxed mice. Exercise causes an increase in the pentose phosphate pathway activity in the floxed mice which is mitigated in the c-Myc KO mice. Exercised floxed mice showed an increased lactate uptake and utilisation into the TCA cycle whereas c-Myc KO mice had decreased reliance on lactate.
Conclusion – Knock-out of c-Myc alters glucose contribution to the TCA cycle and affects the diversion of glycolytic intermediates into pathways of intermediary metabolism important for anabolic growth and adaptation to stress. These results provide new insight into the rewiring of glucose carbon metabolism in the hypertrophied heart that is in part driven by c-Myc. Understanding adaptive remodelling pathways that drive cardiac hypertrophy may help lead to better treatments for preventing heart failure.
| Date of Award | 1 Dec 2023 |
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| Original language | English |
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| Supervisor | Ajay Shah (Supervisor) & Celio Xavier Da Costa Dos Santos (Supervisor) |