{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T13:30:31Z","timestamp":1773754231696,"version":"3.50.1"},"reference-count":24,"publisher":"American Physiological Society","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Cell Physiology"],"published-print":{"date-parts":[[2006,4]]},"abstract":"<jats:p> The repeated elevation of cytosolic Ca<jats:sup>2+<\/jats:sup> concentration ([Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>) above resting levels during contractile activity has been associated with long-lasting muscle fatigue. The mechanism underlying this fatigue appears to involve elevated [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> levels that induce disruption of the excitation-contraction (E-C) coupling process at the triad junction. Unclear, however, are which aspects of the activity-related [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> changes are responsible for the deleterious effects, in particular whether they depend primarily on the peak [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> reached locally at particular sites or on the temporal summation of the increased [Ca<jats:sup>2+<\/jats:sup>] in the cytoplasm as a whole. In this study, we used mechanically skinned fibers from rat extensor digitorum longus muscle, in which the normal E-C coupling process remains intact. The [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> was raised either by applying a set elevated [Ca<jats:sup>2+<\/jats:sup>] throughout the fiber or by using action potential stimulation to induce the release of sarcoplasmic reticulum Ca<jats:sup>2+<\/jats:sup> by the normal E-C coupling system with or without augmentation by caffeine or buffering with BAPTA. Herein we show that elevating [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> in the physiological range of 2\u201320 \u03bcM irreversibly disrupts E-C coupling in a concentration-dependent manner but requires exposure for a relatively long time (1\u20133 min) to cause substantial uncoupling. The effectiveness of Ca<jats:sup>2+<\/jats:sup> released via the endogenous system in disrupting E-C coupling indicates that the relatively high [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> attained close to the release site at the triad junction is a more important factor than the increase in bulk [Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>. Our results suggest that during prolonged vigorous activity, the many repeated episodes of relatively high triadic [Ca<jats:sup>2+<\/jats:sup>] can disrupt E-C coupling and lead to long-lasting fatigue. <\/jats:p>","DOI":"10.1152\/ajpcell.00469.2005","type":"journal-article","created":{"date-parts":[[2005,11,24]],"date-time":"2005-11-24T01:24:33Z","timestamp":1132795473000},"page":"C1199-C1208","source":"Crossref","is-referenced-by-count":45,"title":["Long-lasting muscle fatigue: partial disruption of excitation-contraction coupling by elevated cytosolic Ca<sup>2+<\/sup> concentration during contractions"],"prefix":"10.1152","volume":"290","author":[{"given":"Esther","family":"Verburg","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Travis L.","family":"Dutka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Graham D.","family":"Lamb","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"24","reference":[{"key":"R1","doi-asserted-by":"crossref","unstructured":"Allen DG, Lannergren J, and Westerblad H. 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