Systems modeling reveals that store-operated calcium entry modulates force and fatigue during exercise

The dynamics of calcium ions (Ca2+) in skeletal muscles link electrochemical activation and contractile force generation. An improved quantitative understanding of the mechanisms by which Ca2+ dynamics modulate force production is crucial for optimizing muscle performance. 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. However, the mechanistic links between SOCE and sustained force generation in muscle remain unclear. We hypothesize that SOCE regulates force generation during sustained muscle activity by allowing for increased Ca2+ release from the SR. We test this hypothesis with a quantitative biophysical model that simulates the biochemical events of muscle contraction, from initial depolarization at the sarcolemma and 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. We estimate the free parameters in the model by fitting them to experiments that measured sarcolemma membrane voltage and myoplasmic Ca2+ transients in single muscle fibers in vitro. We then test the effects of SOCE inhibition on Ca2+ dynamics and force production and find that the magnitude of myoplasmic Ca2+ and force are lower than in wild-type cells over repetitive stimuli. Finally, we predict the effects of varying the degree of SOCE inhibition during patterns of stimulus chosen to mimic those observed during resistance exercise or high-intensity interval training. These simulations predict a context-dependent relationship between force generation and SOCE, wherein increased SOCE is associated with greater force production during resistance exercise, but worsens the effects of fatigue in certain cases of high-intensity training.