Abstract
Chronic exercise induces beneficial physiological hypertrophy in the heart, offering protection against cardiovascular and metabolic ailments. Distinguishing its molecular mechanisms from pathological hypertrophy can guide potential treatments. While recent studies emphasise intermediary metabolism's role in cardiac remodelling under stress, its part in exercise-induced hypertrophy is underexplored. This research probes the metabolic pathways in exercise- induced cardiac hypertrophy using mice subjected to four weeks of voluntary wheel running.In this thesis, we employed in vivo stable isotope tracing of glucose to investigate how chronic exercise impacts metabolic adaptation across multiple organs at rest. We observed increased TCA flux in the gastrocnemius muscle and liver, elevated ketogenesis in the liver, and enhanced ketone body metabolism in the heart and kidney post-exercise. Detailed ex vivo perfusion studies in mice revealed decreased glycolysis and hexosamine biosynthesis pathway flux in exercise-trained hearts. Exercise also activated the pentose phosphate pathway (PPP), as evidenced by enzyme upregulation and increased NADPH levels. At the TCA cycle, exercise training led to lower glucose but higher lactate contributions, with palmitate flux remaining unchanged. Given PKM2's known role in regulating PPP metabolism and pathological cardiac hypertrophy, we examined its impact by creating cardiomyocyte- specific PKM2 knockout (csPKM2 KO) mice. These mice showed altered glucose metabolism and reduced hypertrophic growth in response to exercise training, compared to their flox- controlled littermates. These findings suggest a potential role for PKM2 in exercise-induced metabolic adaptation and hypertrophic remodelling.
In conclusion, this thesis delineates the metabolic changes in organs under exercise-induced hypertrophy. PKM2 emerges as pivotal for heart growth, potentially steering metabolic adaptation. Our insights enhance the comprehension of metabolic shifts from exercise and pave the way for therapeutic advances in cardiometabolic health.
| Date of Award | 1 Sept 2024 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Ajay Shah (Supervisor) & Celio Xavier Da Costa Dos Santos (Supervisor) |