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Reduced length-dependent cross-bridge recruitment in skinned fiber preparations of human failing myocardium

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Abstract

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 Ca2+-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 µm, α-actinin staining). The MYO/tension ratio was analyzed as a parameter characterizing myofibrillar energetics. At a sarcomere length of 1.9 µm, the Ca2+ sensitivity of tension was significantly increased in human failing compared to non-failing myocardium. In human non-failing myocardium, maximal Ca2+-activated tension [1.9 µm vs. 2.1 µm, 23.7 (1.9) vs. 28.3 (1.9) mN/mm2] and the Ca2+ sensitivity of tension [EC50Ca2+ (pCa): 5.67 (0.06) vs. 7.07 (0.11)] were increased by increasing sarcomere length. This was accompanied by an enhancement in Ca2+-dependent MYO [+72 (11) vs. +101 (9) µM ADP/s] as well as an increase in the Ca2+-sensitivity of MYO [EC50Ca2+ (pCa): 5.84 (0.08) vs. 6.86 (0.08)]. In human failing myocardium, only Ca2+ sensitivity of tension (but not of MYO) increased. Tension cost was increased in failing vs. non-failing tissue [1.9 µm: 4.18 (0.06) vs. 3.53 (0.06) (mN·s)/(mm2·µM ADP); 2.1 µm: 4.28 (0.13) vs. 3.52 (0.05) (mN·s)/(mm2·µM ADP)]. We concluded that, in human failing myocardium, the length-dependent force generation may be blunted due to an already increased Ca2+ affinity of troponin C as well as an impairment of length-dependent cross-bridge recruitment.

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Acknowledgements

We are indebted to our colleagues of the Departments of the Cardiothoracic Surgery of the University of Cologne (Director: Professor Dr. R.E. de Vivie) and Munich (Director: Professor Dr. B. Reichart) for providing us with human myocardial samples. The authors thank Mrs. Sabine Danneschewski and Katja Rössler for their excellent technical help. This study was supported by the Deutsche Forschungsgemeinschaft (R.H.G.S.) and the Köln Fortune Program/faculty of Medicine, University of Cologne (K.B.).

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Correspondence to Robert H. G. Schwinger.

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Brixius, K., Savidou-Zaroti, P., Bloch, W. et al. Reduced length-dependent cross-bridge recruitment in skinned fiber preparations of human failing myocardium. Eur J Appl Physiol 89, 249–256 (2003). https://doi.org/10.1007/s00421-002-0782-2

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