{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T14:53:10Z","timestamp":1790779990935,"version":"4.1.0"},"reference-count":63,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2020,9,21]],"date-time":"2020-09-21T00:00:00Z","timestamp":1600646400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005350","name":"Centrum f\u00f6r idrottsforskning","doi-asserted-by":"publisher","award":["P2019\u20100060"],"award-info":[{"award-number":["P2019\u20100060"]}],"id":[{"id":"10.13039\/501100005350","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005350","name":"Centrum f\u00f6r idrottsforskning","doi-asserted-by":"publisher","award":["FO2018\u20100019"],"award-info":[{"award-number":["FO2018\u20100019"]}],"id":[{"id":"10.13039\/501100005350","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2018\u201002576"],"award-info":[{"award-number":["2018\u201002576"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Muscle weakness is a common symptom in numerous diseases and a regularly occurring problem associated with ageing. Prolonged low\u2010frequency force depression (PLFFD) is a form of exercise\u2010induced skeletal muscle weakness observed after exercise. Three different intramuscular mechanisms underlying PLFFD have been identified: decreased sarcoplasmic reticulum Ca<jats:sup>2+<\/jats:sup> release, decreased myofibrillar Ca<jats:sup>2+<\/jats:sup> sensitivity, and myofibrillar dysfunction. We here used these three forms of PLFFD as models to study the effectiveness of a fast skeletal muscle troponin activator, CK\u20102066260, to mitigate muscle weakness.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Experiments were performed on intact single muscle fibres or fibre bundles from mouse flexor digitorum brevis, which were stimulated with electrical current pulses, while force and the free cytosolic [Ca<jats:sup>2+<\/jats:sup>] ([Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>) were measured. PLFFD was induced by three different stimulation protocols: (i) repeated isometric contractions at low intensity (350\u00a0ms tetani given every 5\u00a0s for 100 contractions); (ii) repeated isometric contractions at high intensity (250\u00a0ms tetani given every 0.5\u00a0s for 300 contractions); and (iii) repeated eccentric contractions (350\u00a0ms tetani with 20% length increase given every 20\u00a0s for 10 contractions). The extent and cause of PLFFD were assessed by comparing the force\u2013[Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub> relationship at low (30\u00a0Hz) and high (120\u00a0Hz) stimulation frequencies before (control) and 30\u00a0min after induction of PLFFD, and after an additional 5\u00a0min of rest in the presence of CK\u20102066260 (10\u00a0\u03bcM).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Prolonged low\u2010frequency force depression following low\u2010intensity and high\u2010intensity fatiguing contractions was predominantly due to decreased sarcoplasmic reticulum Ca<jats:sup>2+<\/jats:sup> release and decreased myofibrillar Ca<jats:sup>2+<\/jats:sup> sensitivity, respectively. CK\u20102066260 exposure resulted in marked increases in 30\u00a0Hz force from 52\u00a0\u00b1\u00a016% to 151\u00a0\u00b1\u00a013% and from 6\u00a0\u00b1\u00a04% to 98\u00a0\u00b1\u00a040% of controls with low\u2010intensity and high\u2010intensity contractions, respectively. Following repeated eccentric contractions, PLFFD was mainly due to myofibrillar dysfunction, and it was not fully reversed by CK\u20102066260 with 30\u00a0Hz force increasing from 48\u00a0\u00b1\u00a08% to 76\u00a0\u00b1\u00a06% of the control.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The fast skeletal muscle troponin activator CK\u20102066260 effectively mitigates muscle weakness, especially when it is caused by impaired activation of the myofibrillar contractile machinery due to either decreased sarcoplasmic reticulum Ca<jats:sup>2+<\/jats:sup> release or reduced myofibrillar Ca<jats:sup>2+<\/jats:sup> sensitivity.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12624","type":"journal-article","created":{"date-parts":[[2020,9,21]],"date-time":"2020-09-21T09:33:25Z","timestamp":1600680805000},"page":"1747-1757","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Fast skeletal muscle troponin activator CK\u20102066260 mitigates skeletal muscle weakness independently of the underlying cause"],"prefix":"10.1002","volume":"11","author":[{"given":"Arthur J.","family":"Cheng","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology Karolinska Institutet  Stockholm Sweden"},{"name":"School of Kinesiology and Health Science, Faculty of Health York University  Toronto Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Str\u00f6m","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darren T.","family":"Hwee","sequence":"additional","affiliation":[{"name":"Research and Early Development Cytokinetics, Inc.  South San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fady I.","family":"Malik","sequence":"additional","affiliation":[{"name":"Research and Early Development Cytokinetics, Inc.  South San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8180-3029","authenticated-orcid":false,"given":"H\u00e5kan","family":"Westerblad","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology Karolinska Institutet  Stockholm 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