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

The dynamics of calcium ions (Ca2+) in skeletal muscles link electrochemical activation and contractile force generation. Recent experimental data suggest that store-operated Ca2+ entry (SOCE), the process of extracellular Ca2+ influx upon depletion of Ca2+ 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 Ca2+ 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 Ca2+ release from the SR to Ca2+ binding and force generation throughout the myoplasm. We also consider the balance between Ca2+ removal from the myoplasm and SOCE through the T-tubule membrane, along with mitochondrial uptake of free Ca2+ and phosphate. We use the model to test the effects of SOCE inhibition on force production. The magnitude of myoplasmic Ca2+ and force are 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.