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Acidosis affects muscle contraction by slowing the rates myosin attaches to and detaches from actin

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The loss of muscle force and power during fatigue from intense contractile activity is associated with, and likely caused by, elevated levels of phosphate (\(\mathrm {P}_{\mathrm{i}}\)) and hydrogen ions (decreased pH). To understand how these deficits in muscle performance occur at the molecular level, we used direct measurements of mini-ensembles of myosin generating force in the laser trap assay at pH 7.4 and 6.5. The data are consistent with a mechanochemical model in which a decrease in pH reduces myosin’s detachment from actin (by slowing ADP release), increases non-productive myosin binding (by detached myosin rebinding without a powerstroke), and reduces myosin’s attachment to actin (by slowing the weak-to-strong binding transition). Additional support of this mechanism is found by incorporating it into a branched pathway model for the effects of \(\mathrm {P}_{\mathrm{i}}\) on myosin’s interaction with actin. Including pH-dependence in one additional parameter (acceleration of \(\mathrm {P}_{\mathrm{i}}\)-induced detachment), the model reproduces experimental measurements at high and low pH, and variable \(\mathrm {P}_{\mathrm{i}}\), from the single molecule to large ensemble levels. Furthermore, when scaled up, the model predicts force-velocity relationships that are consistent with muscle fiber measurements. The model suggests that reducing pH has two opposing effects, a decrease in attachment favoring a decrease in muscle force and a decrease in detachment favoring an increase in muscle force. Depending on experimental details, the addition of \(\mathrm {P}_{\mathrm{i}}\) can strengthen one or the other effect, resulting in either synergistic or antagonistic effects. This detailed molecular description suggests a molecular basis for contractile failure during muscle fatigue.

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This work was funded by the National Science Foundation (DMS-1413185).

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Correspondence to Sam Walcott.

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This work is supported, in part, by NSF DMS-1413185 to SW.

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Jarvis, K., Woodward, M., Debold, E.P. et al. Acidosis affects muscle contraction by slowing the rates myosin attaches to and detaches from actin. J Muscle Res Cell Motil 39, 135–147 (2018). https://doi.org/10.1007/s10974-018-9499-7

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  • Fatigue
  • Optical trap
  • Modeling
  • Phosphate