Journal Article

A human skeletal muscle cross‐bridge model to characterize the role of metabolite accumulation in muscle fatigue

Erol, Muhammet Enes, Wallqvist, Anders, Layec, Gwenael, Hendry, John I., Debold, Edward P., Pannala, Venkat R., Tewari, Shivendra G.

2025

Overview

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. What is the central question of this study? Force generation in skeletal muscles is driven by ATP hydrolysis and thereby results in the accumulation of its metabolite byproducts, such as ADP, Pi and H+, which can lead to muscle fatigue during intense exercise: what are the individual contributions of each of these metabolites to muscle fatigue development and the underlying mechanisms? What is the main finding and its importance? Using 31P‐MRS and electromyography data from exercising humans and a computational model, we demonstrate that Pi accumulation inhibits force generation by hindering actin–myosin cross‐bridge cycling during intense exercise. The developed skeletal muscle model helps in understanding the role of metabolite accumulation in muscle fatigue development.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Actin / Adenosine Diphosphate - metabolism / Adult / cross‐bridge cycle / Electromyography / Electromyography - methods / Exercise - physiology / Fatigue / Female / Humans / Hydrogen / Magnetic resonance spectroscopy / Male / Metabolites / Models, Biological / Muscle contraction / Muscle Contraction - physiology / Muscle fatigue / Muscle Fatigue - physiology / muscle force generation / Muscle, Skeletal - metabolism / Muscle, Skeletal - physiology / musculoskeletal modelling / Musculoskeletal system / Myosin / Phosphates - metabolism / Plantar flexion / Protons / Sensitivity analysis / Skeletal muscle / skeletal muscle fatigue / Young Adult / Young adults