Cross-bridge model-based quantification of muscle metabolite alterations leading to fatigue during all-out knee extension exercise

Intense physical exercise is associated with high energy demands and muscle metabolite changes that affect force generation, leading to muscle fatigue. Although these changes are well characterized in humans, their contribution to muscle fatigue is not clearly understood. Furthermore, we lack experimental methodologies for a systems-level exploration of these changes that occur during intense exercise to understand the mechanisms behind muscle fatigue development. In this study, we updated our previously developed human skeletal muscle model to include new proton-binding mechanisms and adapted it to study fatigue development during an intense all-out knee extension exercise. We contextualized and parameterized the updated model to simulate muscle force generation and muscle metabolite alterations, using motor unit recruitment data obtained from human subjects performing an all-out knee extension exercise. Our model predictions showed that nullifying the observed decline in motor unit recruitment during all-out exercise was not sufficient to stop fatigue development, as the force recovered only by 13%, and suggested that other factors may play a role. We found that the accumulation of inorganic phosphate (P i ) and protons (H + ), both individually (P i by ∼9% and H + by ∼31%) and synergistically (∼42%), were the main contributing factors at the cross-bridge level that inhibited force generation during all-out exercise. Our model simulations showed that force generation was more sensitive to H + than P i during an all-out knee extension exercise, with elevated P i levels promoting actin-myosin detachment and elevated H + levels preventing the formation of strongly bound cross-bridge states. Furthermore, our computational analysis revealed that the accumulation of H + during an all-out knee extension exercise is the key contributing factor responsible for fatigue development as compared to P i during a constant-power plantar flexion exercise.