Systems modeling of mitochondrial dynamics in different exercise regimes

Exercise stimulates skeletal muscle signaling and mitochondrial metabolism. Emerging evidence shows that mitochondrial dynamics (i.e., fission and fusion) could be regulated by exercise. Yet, there are knowledge gaps on the following questions: (i) which upstream signals are necessary and sufficient to bias mitochondria toward fission versus fusion? (ii) How does cellular energy status and ROS partition control between DRP1 and MFN/OPA1? And (iii) which combinations of intensity and duration produce similar cytosolic signals but distinct mitochondrial remodeling? To address these gaps, we developed an integrative computational framework that connects exercise regimens to mitochondria fission-fusion machinery by linking blood-myofiber energetics in cytosol and mitochondria to skeletal muscle signaling network. The influence of three exercise regimen (i.e., sprint, resistance, and endurance) on mitochondrial fission and fusion was simulated. Classified qualitative validation of signaling network model against studies not used in developing the model achieved 80% accuracy. The model predicts regimen-specific dynamics starting with acute DRP1-driven fission during exercise followed by MFN1/2–OPA1-mediated re-fusion as energy stress declines, consistent with a cyclical triage-then-rebuild paradigm. Changes are most pronounced and sustained with endurance, sharp but brief with sprint, and minimal with resistance. Global sensitivity analysis identified AMPK/PGC-1α→MFN1/2 as dominant fusion drivers, ROS and AMPK→MFF/DRP1 as primary fission switches, and Ca²⁺-calmodulin, ERK, and LKB1/AMPK as shared regulators of fission and fusion. Our model also predicts that an endurance base, augmented with 1–2 weekly high intensity interval traning (HIIT)/ sprint interval training (SIT) sessions could maximize AMPK-ROS pulses and mitochondrial fission-fusion. This framework unifies muscle’s signaling logic with the energetic state to explain how intensity-volume combinations, bout spacing, and kinase modulation tune mitochondrial remodeling, yielding testable predictions for optimizing training and adjuvant therapies for enhanced human performance.