MODULATION OF CONTRACTILITY IN HUMAN CARDIAC-HYPERTROPHY BY MYOSIN ESSENTIAL LIGHT-CHAIN ISOFORMS

Cardiac hypertrophy is an adaptive response that normalizes wall stres s and compensates for increased workload. It is accompanied by distinc t qualitative and quantitative changes in the expression of protein is oforms concerning contractility, intracellular Ca2+-homeostasis and me tabolism. Changes in the myosin subunit isoform expression improves co ntractility by an increase in force generation at a given Ca2+-concent ration (increased Ca2+-sensitivity) and by improving the economy of th e chemo-mechanical transduction process per amount of utilised ATP (in creased duty ratio). In the human atrium this is achieved by partial r eplacement of the endogenous fast myosin by the ventricular slow-type heavy and light chains. In the hypertrophic human ventricle the slow-t ype beta-myosin heavy chains remain unchanged, but the ectopic express ion of the atrial myosin essential light chain (ALC1) partially replac es the endogenous ventricular isoform (VLC1). The ventricular contract ile apparatus with myosin containing ALC1 is characterised by faster c ross-bridge kinetics, a higher Ca2+-sensitivity of force generation an d an increased duty ratio. The mechanism for cross-bridge modulation r elies on the extended Ala-Pro-rich N-terminus of the essential light c hains of which the first eleven residues interact with the C-terminus of actin. A change in charge in this region between ALC1 and VLC1 expl ains their functional difference. The intracellular Ca2+-handling may be impaired in heart failure, resulting in either higher or lower cyto solic Ca2+-levels. Thus the state of the cardiomyocyte determines whet her this hypertrophic adaptation remains beneficial or becomes detrime ntal during failure. Also discussed are the effects on contractility o f long-term changes in isoform expression of other sarcomeric proteins . Positive and negative modulation of contractility by short-term phos phorylation reactions at multiple sites in the myosin regulatory light chain, troponin-I, troponin-T, alpha-tropomyosin and myosin binding p rotein-C are considered in detail. (C) 1998 Elsevier Science B.V.