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Many cellular and molecular changes coincide with muscle fatigue, including a simultaneous increase in both phosphate (Pi) and acidity (pH). The effect of pH and Pi on muscle at the molecular level remains unclear, partly because although pH and Pi cause observable changes in whole muscle fibers, Pi has little effect on single molecule measurements. To better understand the combined effects of pH and Pi on muscle contraction, we first developed a minimal experimental system which shows both phosphate and pH dependence. We then analyzed these experimental results using a mathematical model and Monte Carlo simulations. By including just a few minimal changes in our model, we are able to replicate Pi and pH dependence in experimental measurements from the single molecule to large ensemble levels. Further, the model is able to predict pH and Pi dependent changes in larger scale measurements of peak power, isometric force, and unloaded shortening velocity that have been measured in whole muscle fibers. Our model is able to replicate experimental results and explain conflicting experimental findings, and thus provides molecular insight into the process of fatigue.

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