© 1998 by European Society of Cardiology
Copyright © 1998, European Society of Cardiology
Modulation of contractility in human cardiac hypertrophy by myosin essential light chain isoforms
aInstitute of Pharmacology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
bMax-Delbrück-Center for Molecular Medicine, D-13122 Berlin, Germany
* Corresponding author. Tel.: (+41-1) 635 5919; fax: (+41-1) 635 5708; e-mail: schaub@pharma.unizh.ch
Cardiac hypertrophy is an adaptive response that normalizes wall stress and compensates for increased workload. It is accompanied by distinct qualitative and quantitative changes in the expression of protein isoforms concerning contractility, intracellular Ca2+-homeostasis and metabolism. Changes in the myosin subunit isoform expression improves contractility by an increase in force generation at a given Ca2+-concentration (increased Ca2+-sensitivity) and by improving the economy of the chemo-mechanical transduction process per amount of utilised ATP (increased duty ratio). In the human atrium this is achieved by partial replacement of the endogenous fast myosin by the ventricular slow-type heavy and light chains. In the hypertrophic human ventricle the slow-type β-myosin heavy chains remain unchanged, but the ectopic expression of the atrial myosin essential light chain (ALC1) partially replaces the endogenous ventricular isoform (VLC1). The ventricular contractile apparatus with myosin containing ALC1 is characterised by faster cross-bridge kinetics, a higher Ca2+-sensitivity of force generation and an increased duty ratio. The mechanism for cross-bridge modulation relies on the extended Ala–Pro-rich N-terminus of the essential light chains of which the first eleven residues interact with the C-terminus of actin. A change in charge in this region between ALC1 and VLC1 explains their functional difference. The intracellular Ca2+-handling may be impaired in heart failure, resulting in either higher or lower cytosolic Ca2+-levels. Thus the state of the cardiomyocyte determines whether this hypertrophic adaptation remains beneficial or becomes detrimental during failure. Also discussed are the effects on contractility of long-term changes in isoform expression of other sarcomeric proteins. Positive and negative modulation of contractility by short-term phosphorylation reactions at multiple sites in the myosin regulatory light chain, troponin-I, troponin-T, 
-tropomyosin and myosin binding protein-C are considered in detail.
KEYWORDS Cardiac hypertrophy; Heart failure; Cross-bridge kinetics; Contractility; Myosin heavy chain; Myosin light chain; Ca2+-sensitivity–tension relation
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