Review Modulation of contractility in human cardiac hypertrophy by myosin essential light chain isoforms

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 Ca2q-homeostasis and metabolism. Changes in the myosin subunit isoform expression improves contractility by an increase in force generation at a given 2q 2q.Ca-concentration increased Ca-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 b-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 Ca2q-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 Ca2q-handling may be impaired in heart failure, resulting in either higher or lower cytosolic Ca2q-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-ter