{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T05:56:07Z","timestamp":1787637367569,"version":"build-2736575974"},"posted":{"date-parts":[[2025,5,27]]},"group-title":"Systems Biology","reference-count":130,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T00:00:00Z","timestamp":1748304000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Wu Tsai Human Performance Alliance at UCSD"},{"award":["EEC-2127509"],"award-info":[{"award-number":["EEC-2127509"]}],"id":[{"id":"https:\/\/ror.org\/021nxhr62","id-type":"ROR","asserted-by":"publisher"}]},{"award":["1K99GM162992-01A1"],"award-info":[{"award-number":["1K99GM162992-01A1"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The dynamics of calcium ions (Ca\n                  <jats:sup>2+<\/jats:sup>\n                  ) in skeletal muscles link electrochemical activation and contractile force generation. Recent experimental data suggest that store-operated Ca\n                  <jats:sup>2+<\/jats:sup>\n                  entry (SOCE), the process of extracellular Ca\n                  <jats:sup>2+<\/jats:sup>\n                  influx upon depletion of Ca\n                  <jats:sup>2+<\/jats:sup>\n                  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 Ca\n                  <jats:sup>2+<\/jats:sup>\n                  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 Ca\n                  <jats:sup>2+<\/jats:sup>\n                  release from the SR to Ca\n                  <jats:sup>2+<\/jats:sup>\n                  binding and force generation throughout the myoplasm. We also consider the balance between Ca\n                  <jats:sup>2+<\/jats:sup>\n                  removal from the myoplasm and SOCE through the T-tubule membrane, along with mitochondrial uptake of free Ca\n                  <jats:sup>2+<\/jats:sup>\n                  and phosphate. We use the model to test the effects of SOCE inhibition on force production. The magnitude of myoplasmic Ca\n                  <jats:sup>2+<\/jats:sup>\n                  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 \u2013 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.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Key points<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>\n                        Store-operated calcium entry (SOCE) provides a mechanism for calcium ion (Ca\n                        <jats:sup>2+<\/jats:sup>\n                        ) influx following depletion of Ca\n                        <jats:sup>2+<\/jats:sup>\n                        from intracellular stores such as the sarcoplasmic reticulum (SR).\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Recent experiments suggest that SOCE is an important modulator of contractile force generation in skeletal muscle.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        Here, we develop a computational model of Ca\n                        <jats:sup>2+<\/jats:sup>\n                        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.\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>\n                        Our model predicts that increasing SOCE leads to enhanced force over periods of repeated stimuli during resistance exercise due to sustained Ca\n                        <jats:sup>2+<\/jats:sup>\n                        release.\n                      <\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>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.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>First author profile<\/jats:title>\n                  <jats:p>Emmet 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.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Abstract figure<\/jats:title>\n                  <jats:p>\n                    This 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 \u2013 increased crossbridge cycling due to elevated myoplasmic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    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.\n                  <\/jats:p>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"655415v3_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2025.05.22.655415","type":"posted-content","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T09:30:22Z","timestamp":1748338222000},"source":"Crossref","is-referenced-by-count":5,"title":["Interplay between store-operated calcium entry and mitochondrial phosphate handling modulates force and fatigue during exercise"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6070-805X","authenticated-orcid":false,"given":"Emmet A.","family":"Francis","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University of California San Diego, La Jolla, CA, USA"},{"name":"Department of Mechanical and Aerospace Engineering, University of California San Diego, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3560-6976","authenticated-orcid":false,"given":"Juliette","family":"Hamid","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California San Diego, La Jolla, CA, USA"},{"name":"Department of Mechanical and Aerospace Engineering, University of California San Diego, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2824-301X","authenticated-orcid":false,"given":"Anusha","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Mechanical and Aerospace Engineering, University of California San Diego, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5953-4347","authenticated-orcid":false,"given":"Padmini","family":"Rangamani","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California San Diego, La Jolla, CA, USA"},{"name":"Department of Mechanical and Aerospace Engineering, University of California San Diego, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026072719550662000_2025.05.22.655415v3.1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1970.sp009139"},{"key":"2026072719550662000_2025.05.22.655415v3.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2022.05.006"},{"key":"2026072719550662000_2025.05.22.655415v3.3","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.2001.t01-1-00657.x"},{"key":"2026072719550662000_2025.05.22.655415v3.4","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00015.2007"},{"key":"2026072719550662000_2025.05.22.655415v3.5","doi-asserted-by":"crossref","unstructured":"David G Allen and Sofie Trajanovska . 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