Elucidating the myocardial energy demand-supply-production feedback system

This project develops a predictive, multiscale computational framework to elucidate the myocardium’s energy demand–supply–production feedback system and to identify the primary mechanisms that govern cardiac metabolic and functional homeostasis. The work addresses a gap in understanding how blood flow, cardiac mechanics and mitochondrial energetics interact through multiple interactive pathways to maintain energy homeostasis in the heart. The core objective is to encode the primary system elements responsible for maintaining myocardial homeostasis into an integrative model spanning organelle physiology to whole-organ mechanics, and to challenge that model with novel experimental data obtained across biological spatial scales.

Much of the available evidence implicates metabolic signals as drivers of the system response to perturbations that press against homeostatic mechanisms. One illustrative example pursued in this study is mitochondrial oxidative stress: mitochondrial free radical production can disrupt vasoactive components, impair blood supply, and thereby push the system into a deleterious feedback loop. To elucidate how such phenomena contribute to mechanical function, the project combines model development, experimental calibration and validation, and systematic perturbation studies. The work is organized into three interlinked aims. First, the team will develop a computational model that integrates mechanistic descriptors of mitochondrial energetics with coronary blood flow regulation and multiscale tissue mechanics. This integration is designed to elucidate the coupling between cardiac mechanics, cellular and organelle metabolism, and blood flow regulation across scales. Second, the project will perform experiments specifically intended to calibrate and validate the model, using novel data that span biological spatial scales so the model is constrained and tested against physiologically relevant measurements.

These calibration and validation experiments will enable the model to identify causal relationships linking microvasculature function and mitochondrial energetics rather than relying solely on correlational evidence. Third, once validated, the model will be used to characterize the system response to a multitude of perturbations, with the explicit goal of investigating essential feedback loops that control energy supply and demand in the myocardium. By systematically probing how perturbations in mitochondrial function, oxidative stress, or vascular responsiveness propagate through the coupled system, the study aims to identify the major contributing mechanisms that influence overall system behavior.

The project commits to open science: the developed code and model will be made publicly available. By integrating mechanistic modeling with targeted experimental validation and by making tools openly accessible, this work seeks to provide a complete picture of the fundamental mechanisms that govern cardiac metabolic and functional homeostasis and to offer a platform for future hypothesis testing and translational exploration.