Increased Ca-sensitivity of the contractile apparatus in end-stage human heart failure results from altered phosphorylation of contractile proteins

Abstract

The increased Ca(2+)-responsiveness of the contractile apparatus in end-stage failing human hearts cannot be explained by a shift in contractile protein isoforms, but results from the complex interplay between changes in the phosphorylation status of MLC-2 and TnI.

Myofibrillar remodelling in cardiac hypertrophy, heart failure and cardiomyopathies

“…Recent results suggest that the difference in Ca 2+ responsiveness in the failing heart does not reflect intrinsic differences in the protein isoform composition, but rather represents a change in the endogenous phosphorylation status of thin and thick filament proteins (91,108,109). Such an alteration may be determined by the presence of different amounts of kinases, such as the cyclic AMP-dependent protein kinase A (PKA), protein kinase C (PKC) and myosin light chain kinase (MLCK), as well as phosphatases, in the failing myocardium.…”

Myosin light chain phosphorylation to the rescue

“…This finding is clinically important not only for patients with HCM who have the D166V mutation but also for other patients with mutations elsewhere in the RLC and for patients with end-stage heart failure, in whom significantly reduced RLC phosphorylation has also been reported (20). Although constitutive RLC phosphorylation by introducing an S15D mutation (as done in the mouse) will not be easily feasible in patients, a possible alternative is the manipulation of the activities of either cMLCK (increasing it) or cMLCP (lowering it).…”

Transmural Heterogeneity of Cellular Level Power Output Is Reduced in Human Heart Failure

“…Data from rat trabeculae [27] suggest that this phosphorylation gradient would increase Ca 2+ sensitivity in epicardial tissue. However, the situation is complex, because van der Velden et al [28] have shown that increased phosphorylation of MLC-2 decreases pCa 50 values. Unfortunately, MLC-2 phosphorylation was not studied in this work.…”