{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T15:18:09Z","timestamp":1790090289643,"version":"4.0.1"},"reference-count":52,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2016,6,12]],"date-time":"2016-06-12T00:00:00Z","timestamp":1465689600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2016,7,15]]},"abstract":"<jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Genetic mutations in cardiac troponin I (cTnI) are associated with development of hypertrophic cardiomyopathy characterized by myocyte remodelling, disorganization of cytoskeletal proteins and altered energy metabolism.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The L\u2010type Ca<jats:sup>2+<\/jats:sup> channel is the main route for calcium influx and is crucial to cardiac excitation and contraction. The channel also regulates mitochondrial function in the heart by a functional communication between the channel and mitochondria via the cytoskeletal network.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We find that L\u2010type Ca<jats:sup>2+<\/jats:sup> channel kinetics are altered in <jats:italic>cTnI\u2010G203S<\/jats:italic> cardiac myocytes and that activation of the channel causes a significantly greater increase in mitochondrial membrane potential and metabolic activity in <jats:italic>cTnI\u2010G203S<\/jats:italic> cardiac myocytes.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These responses occur as a result of impaired communication between the L\u2010type Ca<jats:sup>2+<\/jats:sup> channel and cytoskeletal protein F\u2010actin, involving decreased movement of actin\u2013myosin and block of the mitochondrial voltage\u2010dependent anion channel, resulting in a \u2018hypermetabolic\u2019 mitochondrial state.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>We propose that L\u2010type Ca<jats:sup>2+<\/jats:sup> channel antagonists, such as diltiazem, might be effective in reducing the cardiomyopathy by normalizing mitochondrial metabolic activity.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Genetic mutations in cardiac troponin I (cTnI) account for 5% of families with hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy is associated with disorganization of cytoskeletal proteins and altered energy metabolism. The L\u2010type Ca<jats:sup>2+<\/jats:sup> channel (I<jats:sub>Ca\u2010L<\/jats:sub>) plays an important role in regulating mitochondrial function. This involves a functional communication between the channel and mitochondria via the cytoskeletal network. We investigate the role of I<jats:sub>Ca\u2010L<\/jats:sub> in regulating mitochondrial function in 25\u2010 to 30\u2010week\u2010old cardiomyopathic mice expressing the human disease\u2010causing mutation Gly203Ser in cTnI (<jats:italic>cTnI\u2010G203S<\/jats:italic>). The inactivation rate of I<jats:sub>Ca\u2010L<\/jats:sub> is significantly faster in <jats:italic>cTnI\u2010G203S<\/jats:italic> myocytes [<jats:italic>cTnI\u2010G203S<\/jats:italic>: \u03c4<jats:sub>1<\/jats:sub>\u00a0=\u00a040.68\u00a0\u00b1\u00a03.22, <jats:italic>n<\/jats:italic>\u00a0=\u00a010 <jats:italic>vs<\/jats:italic>. wild\u2010type (<jats:italic>wt<\/jats:italic>): \u03c4<jats:sub>1<\/jats:sub>\u00a0=\u00a059.05\u00a0\u00b1\u00a06.40, <jats:italic>n<\/jats:italic>\u00a0=\u00a06, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05]. Activation of I<jats:sub>Ca\u2010L<\/jats:sub> caused a greater increase in mitochondrial membrane potential (\u03a8<jats:sub>m<\/jats:sub>, 29.19\u00a0\u00b1\u00a01.85%, <jats:italic>n<\/jats:italic>\u00a0=\u00a015 <jats:italic>vs<\/jats:italic>. <jats:italic>wt<\/jats:italic>: 18.84\u00a0\u00b1\u00a02.01%, <jats:italic>n<\/jats:italic>\u00a0=\u00a010, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05) and metabolic activity (24.40\u00a0\u00b1\u00a06.46%, <jats:italic>n<\/jats:italic>\u00a0=\u00a08 <jats:italic>vs<\/jats:italic>. <jats:italic>wt<\/jats:italic>: 9.98\u00a0\u00b1\u00a01.57%, <jats:italic>n<\/jats:italic>\u00a0=\u00a09, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.05). The responses occurred because of impaired communication between I<jats:sub>Ca\u2010L<\/jats:sub> and F\u2010actin, involving lack of dynamic movement of actin\u2013myosin and block of the mitochondrial voltage\u2010dependent anion channel. Similar responses were observed in precardiomyopathic mice. I<jats:sub>Ca\u2010L<\/jats:sub> antagonists nisoldipine and diltiazem decreased \u03a8<jats:sub>m<\/jats:sub> to basal levels. We conclude that the Gly203Ser mutation leads to impaired functional communication between I<jats:sub>Ca\u2010L<\/jats:sub> and mitochondria, resulting in a \u2018hypermetabolic\u2019 state. This might contribute to development of <jats:italic>cTnI\u2010G203S<\/jats:italic> cardiomyopathy because the response is present in young precardiomyopathic mice. I<jats:sub>Ca\u2010L<\/jats:sub> antagonists might be effective in reducing the cardiomyopathy by altering mitochondrial function.<\/jats:p><\/jats:sec>","DOI":"10.1113\/jp271681","type":"journal-article","created":{"date-parts":[[2016,4,10]],"date-time":"2016-04-10T17:42:00Z","timestamp":1460310120000},"page":"4051-4070","source":"Crossref","is-referenced-by-count":27,"title":["The L\u2010type Ca<sup>2+<\/sup> channel facilitates abnormal metabolic activity in the <i>cTnI\u2010G203S<\/i> mouse model of hypertrophic cardiomyopathy"],"prefix":"10.1113","volume":"594","author":[{"given":"Helena","family":"Viola","sequence":"first","affiliation":[{"name":"School of Anatomy, Physiology and Human Biology The University of Western Australia  Crawley WA Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Johnstone","sequence":"additional","affiliation":[{"name":"School of Anatomy, Physiology and Human Biology The University of Western Australia  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