ORIGINAL RESEARCH article
Front. Physiol.
Sec. Exercise Physiology
Cross-bridge model-based quantification of muscle metabolite alterations leading to fatigue during all-out knee extension exercise
John I. Hendry 1,2
Muhammet Enes Erol 3,4
Gwenael Layec 3,4
Edward P. Debold 3
Anders Wallqvist 1
Venkat R. Pannala 1,2
1. Department of Defense Biotechnology High Performance Computing Software Applications Institute, Defense Health Agency Research & Development, Medical Research and Development Command, Fort Detrick, United States
2. Henry M Jackson Foundation for the Advancement of Military Medicine (HJF), Bethesda, United States
3. Department of Kinesiology, University of Massachusetts Amherst, Amherst, United States
4. School of Health and Kinesiology, University of Nebraska, Omaha, United States
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Abstract
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 (Pi) and protons (H+), both individually (Pi 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 Pi during an all-out knee extension exercise, with elevated Pi 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 Pi during a constant-power plantar flexion exercise.
Summary
Keywords
cross-bridge cycle, inorganic phosphate, Knee extension, Protons, Skeletal muscle fatigue
Received
07 November 2025
Accepted
19 February 2026
Copyright
© 2026 Hendry, Erol, Layec, Debold, Wallqvist and Pannala. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Anders Wallqvist; Venkat R. Pannala
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