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bioRxiv · 10.1101/2025.05.22.655415

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

Francis, E. A.·Hamid, J.·Kumar, A.·Rangamani, P.
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Abstract

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. Key pointsO_LIStore-operated calcium entry (SOCE) provides a mechanism for calcium ion (Ca2+) influx following depletion of Ca2+ from intracellular stores such as the sarcoplasmic reticulum (SR). C_LIO_LIRecent experiments suggest that SOCE is an important modulator of contractile force generation in skeletal muscle. C_LIO_LIHere, we develop a computational model of Ca2+ handling in the myoplasm, SR, and mitochondria and the resulting effects on force generation in skeletal muscle fibers to examine the role of SOCE during extended periods of activity. C_LIO_LIOur model predicts that increasing SOCE leads to enhanced force over periods of repeated stimuli during resistance exercise due to sustained Ca2+ release. C_LIO_LIOur 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. C_LI First author profileEmmet Francis is a K99/R00 awardee in the Rangamani Lab at UC San Diego whose research explores the intersection between cell signaling and mechanics. His doctoral research in the Heinrich Lab at UC Davis examined the role of calcium bursts in neutrophil chemotaxis and phagocytosis. More recently, he has used spatial modeling approaches to shed light on the role of nanoscale membrane curvature and nuclear deformation in YAP/TAZ mechanotransduction. In his own research lab, he plans to use both experiments and computational models to probe the mechanisms of bidirectional mechanotransduction in neutrophils. Abstract figureThis study uses systems modeling to demonstrate a role for SOCE in sustained force generation during exercise. SOCE leads to two competing effects on contractile force in myofibers - increased crossbridge cycling due to elevated myoplasmic Ca2+ enhances force, whereas increased accumulation of myoplasmic phosphate (due to increased ATP hydrolysis) can lead to force reduction (fatigue). The tradeoff between these two effects is modulated by phosphate uptake into mitochondria via the phosphate carrier PiC. Figure created in BioRender. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=74 SRC="FIGDIR/small/655415v3_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@5c9dc9org.highwire.dtl.DTLVardef@7b06b1org.highwire.dtl.DTLVardef@f478c5org.highwire.dtl.DTLVardef@24d321_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Francis, E. A., Hamid, J., Kumar, A., Rangamani, P.. 2025-05-27. Systems modeling reveals that store-operated calcium entry modulates force and fatigue during exercise. https://doi.org/10.1101/2025.05.22.655415

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