{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T07:25:16Z","timestamp":1790234716485,"version":"4.1.0"},"reference-count":39,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2009,1,2]]},"abstract":"<jats:p>\n            Previous studies demonstrated increased fatty acid uptake and metabolism in MHC-FATP transgenic mice that overexpress fatty acid transport protein (FATP)1 in the heart under the control of the \u03b1-myosin heavy chain (\u03b1-MHC) promoter. Doppler tissue imaging and hemodynamic measurements revealed diastolic dysfunction, in the absence of changes in systolic function. The experiments here directly test the hypothesis that the diastolic dysfunction in MHC-FATP mice reflects impaired ventricular myocyte contractile function. In vitro imaging of isolated adult MHC-FATP ventricular myocytes revealed that mean diastolic sarcomere length is significantly (\n            <jats:italic>P<\/jats:italic>\n            &lt;0.01) shorter than in wild-type (WT) cells (1.79\u00b10.01 versus 1.84\u00b10.01 \u03bcm). In addition, the relaxation rate (dL\/dt) is significantly (\n            <jats:italic>P<\/jats:italic>\n            &lt;0.05) slower in MHC-FATP than WT myocytes (1.58\u00b10.09 versus 1.92\u00b10.13 \u03bcm\/s), whereas both fractional shortening and contraction rates are not different. Application of 40 mmol\/L 2,3-butadionemonoxime (a nonspecific ATPase inhibitor that relaxes actin\u2013myosin interactions) increased diastolic sarcomere length in both WT and MHC-FATP myocytes to the same length, suggesting that MHC-FATP myocytes are partially activated at rest. Direct measurements of intracellular Ca\n            <jats:sup>2+<\/jats:sup>\n            revealed that diastolic [Ca\n            <jats:sup>2+<\/jats:sup>\n            ]\n            <jats:sub>i<\/jats:sub>\n            is unchanged in MHC-FATP myocytes and the rate of calcium removal is unexpectedly faster in MHC-FATP than WT myocytes. Moreover, diastolic sarcomere length in MHC-FATP and WT myocytes was unaffected by removal of extracellular Ca\n            <jats:sup>2+<\/jats:sup>\n            or by buffering of intracellular Ca\n            <jats:sup>2+<\/jats:sup>\n            with the Ca\n            <jats:sup>2+<\/jats:sup>\n            chelator BAPTA (100 \u03bcmol\/L), indicating that elevated intracellular Ca\n            <jats:sup>2+<\/jats:sup>\n            does not underlie impaired diastolic function in MHC-FATP ventricular myocytes. Functional assessment of skinned myocytes, however, revealed that myofilament Ca\n            <jats:sup>2+<\/jats:sup>\n            sensitivity is markedly increased in MHC-FATP, compared with WT, ventricular cells. In addition, biochemical experiments demonstrated increased expression of the \u03b2-MHC isoform in MHC-FATP, compared with WT ventricles, which likely contributes to the slower relaxation rate observed in MHC-FATP myocytes. Collectively, these data demonstrate that derangements in lipid metabolism in MHC-FATP ventricles, which are similar to those observed in the diabetic heart, result in impaired diastolic function that primarily reflects changes in myofilament function, rather than altered Ca\n            <jats:sup>2+<\/jats:sup>\n            cycling.\n          <\/jats:p>","DOI":"10.1161\/circresaha.108.186809","type":"journal-article","created":{"date-parts":[[2008,11,21]],"date-time":"2008-11-21T02:50:08Z","timestamp":1227235808000},"page":"95-103","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":50,"title":["Ca\n            <sup>2+<\/sup>\n            -Independent Alterations in Diastolic Sarcomere Length and Relaxation Kinetics in a Mouse Model of Lipotoxic Diabetic Cardiomyopathy"],"prefix":"10.1161","volume":"104","author":[{"given":"Thomas P.","family":"Flagg","sequence":"first","affiliation":[{"name":"From the Departments of Cell Biology and Physiology (T.P.F., M.S.R., C.G.N.), Molecular Biology and Pharmacology (J.M.N.), and Internal Medicine (A.K., J.E.S.), Washington University School of Medicine, St Louis, Mo; Institut National de la Sante\u0301 et de la Recherche Me\u0301dicale, U-637 (O.C.), Universite\u0301 Montpellier 1, Unite\u0301 de Formation et de Recherche de Me\u0301decine, Montpellier, France; and Pfizer Global Research &amp; Development (T.E.H., M.A.T., A.B., R.E.N.), Chesterfield, Mo."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Cazorla","sequence":"additional","affiliation":[{"name":"From the Departments of Cell Biology and Physiology (T.P.F., M.S.R., C.G.N.), Molecular Biology and Pharmacology (J.M.N.), and Internal Medicine (A.K., J.E.S.), Washington University School of Medicine, St Louis, Mo; Institut National de la Sante\u0301 et de la Recherche Me\u0301dicale, U-637 (O.C.), Universite\u0301 Montpellier 1, Unite\u0301 de Formation et de Recherche de Me\u0301decine, Montpellier, France; and Pfizer Global Research &amp; Development (T.E.H., M.A.T., A.B., R.E.N.), Chesterfield, Mo."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria S.","family":"Remedi","sequence":"additional","affiliation":[{"name":"From the Departments of Cell Biology and Physiology (T.P.F., M.S.R., C.G.N.), Molecular Biology and Pharmacology (J.M.N.), and Internal Medicine (A.K., J.E.S.), Washington University School of Medicine, St Louis, Mo; Institut National de la Sante\u0301 et de la Recherche Me\u0301dicale, U-637 (O.C.), Universite\u0301 Montpellier 1, Unite\u0301 de Formation et de Recherche de Me\u0301decine, Montpellier, France; and Pfizer Global Research &amp; Development (T.E.H., M.A.T., A.B., R.E.N.), Chesterfield, Mo."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd E.","family":"Haim","sequence":"additional","affiliation":[{"name":"From the Departments of Cell Biology and Physiology (T.P.F., M.S.R., C.G.N.), Molecular Biology and Pharmacology (J.M.N.), and Internal Medicine (A.K., J.E.S.), Washington University School of Medicine, St Louis, Mo; Institut National de la Sante\u0301 et de la Recherche Me\u0301dicale, U-637 (O.C.), Universite\u0301 Montpellier 1, Unite\u0301 de Formation et de Recherche de Me\u0301decine, Montpellier, France; and Pfizer Global Research &amp; Development (T.E.H., M.A.T., A.B., R.E.N.), Chesterfield, Mo."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael A.","family":"Tones","sequence":"additional","affiliation":[{"name":"From the Departments of Cell Biology and Physiology (T.P.F., M.S.R., C.G.N.), Molecular Biology and Pharmacology (J.M.N.), and Internal Medicine (A.K., J.E.S.), Washington University School of Medicine, St Louis, Mo; Institut National de la Sante\u0301 et de la Recherche Me\u0301dicale, U-637 (O.C.), Universite\u0301 Montpellier 1, Unite\u0301 de Formation et de Recherche de Me\u0301decine, Montpellier, France; and Pfizer Global Research &amp; Development (T.E.H., M.A.T., A.B., R.E.N.), Chesterfield, Mo."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Bahinski","sequence":"additional","affiliation":[{"name":"From the Departments of Cell Biology and Physiology (T.P.F., M.S.R., C.G.N.), Molecular Biology and Pharmacology (J.M.N.), and Internal Medicine (A.K., J.E.S.), Washington University School of Medicine, St Louis, Mo; Institut National de la Sante\u0301 et de la Recherche Me\u0301dicale, U-637 (O.C.), Universite\u0301 Montpellier 1, Unite\u0301 de Formation et de Recherche de Me\u0301decine, Montpellier, France; and Pfizer Global Research &amp; Development (T.E.H., M.A.T., A.B., R.E.N.), Chesterfield, Mo."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randal E.","family":"Numann","sequence":"additional","affiliation":[{"name":"From the Departments of Cell Biology and Physiology (T.P.F., M.S.R., C.G.N.), Molecular Biology and Pharmacology (J.M.N.), and Internal Medicine (A.K., J.E.S.), Washington University School of Medicine, St Louis, Mo; Institut National de la Sante\u0301 et de la Recherche Me\u0301dicale, U-637 (O.C.), Universite\u0301 Montpellier 1, Unite\u0301 de Formation et de Recherche de Me\u0301decine, Montpellier, France; and Pfizer Global Research &amp; Development (T.E.H., M.A.T., A.B., R.E.N.), Chesterfield, Mo."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Attila","family":"Kovacs","sequence":"additional","affiliation":[{"name":"From the Departments of Cell Biology and Physiology (T.P.F., M.S.R., C.G.N.), Molecular Biology and Pharmacology (J.M.N.), and Internal Medicine (A.K., J.E.S.), Washington University School of Medicine, St Louis, Mo; Institut National de la Sante\u0301 et de la Recherche Me\u0301dicale, U-637 (O.C.), Universite\u0301 Montpellier 1, Unite\u0301 de Formation et de Recherche de Me\u0301decine, Montpellier, France; and Pfizer Global Research &amp; Development (T.E.H., M.A.T., A.B., R.E.N.), Chesterfield, Mo."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean E.","family":"Schaffer","sequence":"additional","affiliation":[{"name":"From the Departments of Cell Biology and Physiology (T.P.F., M.S.R., C.G.N.), Molecular Biology and Pharmacology (J.M.N.), and Internal Medicine (A.K., J.E.S.), Washington University School of Medicine, St Louis, Mo; Institut National de la Sante\u0301 et de la Recherche Me\u0301dicale, U-637 (O.C.), Universite\u0301 Montpellier 1, Unite\u0301 de Formation et de Recherche de Me\u0301decine, Montpellier, France; and Pfizer Global Research &amp; Development (T.E.H., M.A.T., A.B., R.E.N.), Chesterfield, Mo."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin G.","family":"Nichols","sequence":"additional","affiliation":[{"name":"From the Departments of Cell Biology and Physiology (T.P.F., M.S.R., C.G.N.), Molecular Biology and Pharmacology (J.M.N.), and Internal Medicine (A.K., J.E.S.), Washington University School of Medicine, St Louis, Mo; Institut National de la Sante\u0301 et de la Recherche Me\u0301dicale, U-637 (O.C.), Universite\u0301 Montpellier 1, Unite\u0301 de Formation et de Recherche de Me\u0301decine, Montpellier, France; and Pfizer Global Research &amp; Development (T.E.H., M.A.T., A.B., R.E.N.), Chesterfield, Mo."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanne M.","family":"Nerbonne","sequence":"additional","affiliation":[{"name":"From the Departments of Cell Biology and Physiology (T.P.F., M.S.R., C.G.N.), Molecular Biology and Pharmacology (J.M.N.), and Internal Medicine (A.K., J.E.S.), Washington University School of Medicine, St Louis, Mo; Institut National de la Sante\u0301 et de la Recherche Me\u0301dicale, U-637 (O.C.), Universite\u0301 Montpellier 1, Unite\u0301 de Formation et de Recherche de Me\u0301decine, Montpellier, France; and Pfizer Global Research &amp; Development (T.E.H., M.A.T., A.B., R.E.N.), Chesterfield, Mo."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.107.702795"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/circulationaha.106.679597"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1015328625394"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(97)00047-3"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(03)00625-9"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(97)00144-7"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2006.02.048"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1677\/joe.1.06241"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.55.03.06.db05-1284"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.53.12.3201"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.2000.279.5.E1104"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.2000.279.2.H639"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000154079.20681.b9"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00676.2003"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.04-2066fje"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1994.sp020149"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1161\/circresaha.107.158774"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.res.0000268412.34364.50"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00407.2004"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-007-0394-0"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2828(80)90063-2"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.51.4.1166"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1096\/fj.01-1019fje"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1996.270.1.H24"},{"key":"e_1_3_3_25_2","first-page":"H676","volume":"269","year":"1995","unstructured":"Janssen PM, Hunter WC. 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