Skeletal muscle fatigue is accompanied by the accumulation of metabolites, such as adenosine diphosphate (ADP), inorganic phosphate (Pi), and protons (H+). However, we lack a comprehensive understanding of the contribution of these metabolic changes to the development of muscle fatigue during intense exercise and the underlying mechanisms. To address this gap, we collected data from young adults performing a dynamic (0.75 Hz) plantar flexion exercise to task failure (642 ± 104 s), including in vivo concentrations of metabolites and H+ measured by 31P magnetic resonance spectroscopy as well as muscle activation signals obtained via electromyography. Using these data, we developed and validated a human skeletal muscle model. Our model-based simulations suggested that to continue the plantar flexion exercise at the required power output, muscle activation should progressively increase. In the absence of this increased activation, we observed a reduction in force-generating capacity due to metabolite-mediated inhibition of actin-myosin cross-bridge cycling. Our simulations also showed that Pi reduced force production by 30% when we increased it 50% above the concentrations measured experimentally. A parameter sensitivity analysis suggested that force generation is strongly dependent on the rate of Pi release from the actin-myosin complex, and Pi inhibits force by increasing the rate of actin-myosin detachment. In addition, we proposed an alternative mechanism through which H+ might reduce muscle force generation during exercise. In contrast, elevated ADP levels did not significantly affect force generation. This study provides insight into the impact of metabolite accumulation on force generation and muscle fatigue development.
Keywords: cross‐bridge cycle; muscle force generation; musculoskeletal modelling; plantar flexion; skeletal muscle fatigue.
© 2025 The Author(s). Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.