Reduced length-dependent cross-bridge recruitment in skinned fiber preparations of human failing myocardium.
A depressed activity of myosin ATPase has been described in human failing myocardium. Since alterations in cross-bridge kinetics may affect both systolic and diastolic cardiac function, the present study simultaneously investigated Ca(2+)-dependent tension and actomyosin ATPase activity (MYO) in triton X-skinned fiber preparations of human non-failing (donor hearts, n=8) and failing (dilated cardiomyopathy, n=11) left ventricular myocardium at increasing sarcomeric length (1.9 and 2.1 microm, alpha-actinin staining). The MYO/tension ratio was analyzed as a parameter characterizing myofibrillar energetics. At a sarcomere length of 1.9 microm, the Ca(2+) sensitivity of tension was significantly increased in human failing compared to non-failing myocardium. In human non-failing myocardium, maximal Ca(2+)-activated tension [1.9 microm vs. 2.1 microm, 23.7 (1.9) vs. 28.3 (1.9) mN/mm(2)] and the Ca(2+) sensitivity of tension [EC(50)Ca(2+ )(pCa): 5.67 (0.06) vs. 7.07 (0.11)] were increased by increasing sarcomere length. This was accompanied by an enhancement in Ca(2+)-dependent MYO [+72 (11) vs. +101 (9) microM ADP/s] as well as an increase in the Ca(2+)-sensitivity of MYO [EC(50)Ca(2+ )(pCa): 5.84 (0.08) vs. 6.86 (0.08)]. In human failing myocardium, only Ca(2+) sensitivity of tension (but not of MYO) increased. Tension cost was increased in failing vs. non-failing tissue [1.9 microm: 4.18 (0.06) vs. 3.53 (0.06) (mN.s)/(mm(2). microM ADP); 2.1 microm: 4.28 (0.13) vs. 3.52 (0.05) (mN.s)/(mm(2). microM ADP)]. We concluded that, in human failing myocardium, the length-dependent force generation may be blunted due to an already increased Ca(2+) affinity of troponin C as well as an impairment of length-dependent cross-bridge recruitment.
Laboratory of Muscle Research and Molecular Cardiology, Department of Internal Medicine III, University of Cologne, Joseph-Stelzmann-Strasse 9, 50924 Cologne, Germany.
Klara
K
Brixius
Persephone
P
Savidou-Zaroti
Wilhelm
W
Bloch
Robert H G
RH
Schwinger
D000328:Adult; D002118:Calcium / Q000378:metabolism*; D002311:Cardiomyopathy, Dilated / Q000150:complications / Q000503:physiopathology*; D002478:Cells, Cultured; D005260:Female; D006352:Heart Ventricles / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D007537:Isometric Contraction; D008297:Male; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism; D009218:Myosins / Q000378:metabolism*; D012016:Reference Values; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000503:physiopathology*
D009218:Myosins; D002118:Calcium