Interplay between store-operated calcium entry and mitochondrial phosphate handling modulates force and fatigue...

The dynamics of calcium ions ( ${\text{Ca}}^{2+}$ ) in skeletal muscles link electrochemical activation and contractile force generation. Recent experimental data suggest that store-operated ${\text{Ca}}^{2+}$ entry (SOCE), the process of extracellular ${\text{Ca}}^{2+}$ influx upon the depletion of ${\text{Ca}}^{2+}$ from the sarcoplasmic reticulum (SR), helps delay the onset of muscle fatigue during exercise. We hypothesize that SOCE regulates force generation during prolonged muscle activity by allowing for sustained ${\text{Ca}}^{2+}$ release from the SR. We test this hypothesis with a quantitative biophysical model that simulates the biochemical events of muscle contraction, from depolarization at the T-tubules to ${\text{Ca}}^{2+}$ release from the SR to ${\text{Ca}}^{2+}$ binding and force generation throughout the myoplasm. We also consider the balance between ${\text{Ca}}^{2+}$ removal from the myoplasm and SOCE through the T-tubule membrane, along with mitochondrial uptake of free ${\text{Ca}}^{2+}$ and phosphate. We use the model to test the effects of SOCE inhibition on force production. The magnitude of myoplasmic ${\text{Ca}}^{2+}$ and force is lower in SOCE knockout cells, especially when SOCE reduction is combined with impaired uptake of phosphate by mitochondria. We then test the effects of SOCE during resistance exercise or high-intensity interval training. These simulations predict a context-dependent relationship between force generation and SOCE - increased SOCE is associated with greater force production during resistance exercise but worsens the effects of fatigue in certain cases of high-intensity training. Such SOCE-induced fatigue is attributed to phosphate accumulation in the myoplasm and can be mitigated by increased rates of mitochondrial phosphate uptake. KEY POINTS: Store-operated calcium entry (SOCE) provides a mechanism for calcium ion ( ${\text{Ca}}^{2+}$ ) influx following the depletion of ${\text{Ca}}^{2+}$ from intracellular stores such as the sarcoplasmic reticulum (SR). Recent experiments suggest that SOCE is an important modulator of contractile force generation in skeletal muscle. Here we develop a computational model of ${\text{Ca}}^{2+}$ handling in the myoplasm, SR, and mitochondria and the resulting effects on force generation in skeletal muscle fibres to examine the role of SOCE during extended periods of activity. Our model predicts that increasing SOCE leads to enhanced force over periods of repeated stimuli during resistance exercise due to sustained ${\text{Ca}}^{2+}$ release. Our simulations show a complex relationship between SOCE and force production during high-intensity interval training, with exacerbated phosphate accumulation in the myoplasm leading to force reduction for very high levels of SOCE. This effect can be mitigated by enhanced mitochondrial phosphate uptake.