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Depressed Myocardial Cross-bridge Cycling Kinetics in a Female Guinea Pig Model of Diastolic Heart Failure

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Journal J Gen Physiol
Specialty Physiology
Date 2023 Apr 27
PMID 37102986
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Abstract

Cardiac hypertrophy is associated with diastolic heart failure (DHF), a syndrome in which systolic function is preserved but cardiac filling dynamics are depressed. The molecular mechanisms underlying DHF and the potential role of altered cross-bridge cycling are poorly understood. Accordingly, chronic pressure overload was induced by surgically banding the thoracic ascending aorta (AOB) in ∼400 g female Dunkin Hartley guinea pigs (AOB); Sham-operated age-matched animals served as controls. Guinea pigs were chosen to avoid the confounding impacts of altered myosin heavy chain (MHC) isoform expression seen in other small rodent models. In vivo cardiac function was assessed by echocardiography; cardiac hypertrophy was confirmed by morphometric analysis. AOB resulted in left ventricle (LV) hypertrophy and compromised diastolic function with normal systolic function. Biochemical analysis revealed exclusive expression of β-MHC isoform in both sham control and AOB LVs. Myofilament function was assessed in skinned multicellular preparations, skinned single myocyte fragments, and single myofibrils prepared from frozen (liquid N2) LVs. The rates of force-dependent ATP consumption (tension-cost) and force redevelopment (Ktr), as well as myofibril relaxation time (Timelin) were significantly blunted in AOB, indicating reduced cross-bridge cycling kinetics. Maximum Ca2+ activated force development was significantly reduced in AOB myocytes, while no change in myofilament Ca2+ sensitivity was observed. Our results indicate blunted cross-bridge cycle in a β-MHC small animal DHF model. Reduced cross-bridge cycling kinetics may contribute, at least in part, to the development of DHF in larger mammals, including humans.

References
1.
Krenz M, Sanbe A, Bouyer-Dalloz F, Gulick J, Klevitsky R, Hewett T . Analysis of myosin heavy chain functionality in the heart. J Biol Chem. 2003; 278(19):17466-74. DOI: 10.1074/jbc.M210804200. View

2.
Vitale G, Ferrantini C, Piroddi N, Scellini B, Pioner J, Colombini B . The relation between sarcomere energetics and the rate of isometric tension relaxation in healthy and diseased cardiac muscle. J Muscle Res Cell Motil. 2019; 42(1):47-57. PMC: 7932984. DOI: 10.1007/s10974-019-09566-2. View

3.
Zile M, Brutsaert D . New concepts in diastolic dysfunction and diastolic heart failure: Part I: diagnosis, prognosis, and measurements of diastolic function. Circulation. 2002; 105(11):1387-93. DOI: 10.1161/hc1102.105289. View

4.
Sadayappan S, Gulick J, Klevitsky R, Lorenz J, Sargent M, Molkentin J . Cardiac myosin binding protein-C phosphorylation in a {beta}-myosin heavy chain background. Circulation. 2009; 119(9):1253-62. PMC: 2656413. DOI: 10.1161/CIRCULATIONAHA.108.798983. View

5.
van der Velden J, de Tombe P . Heart failure: a special issue. Pflugers Arch. 2014; 466(6):1023. PMC: 4100790. DOI: 10.1007/s00424-014-1531-1. View