Suppression of lusitropy as a disease mechanism in cardiomyopathies

Abstract

In cardiac muscle the action of adrenaline on β1 receptors of heart muscle cells is essential to adjust cardiac output to the body’s needs. Adrenergic activation leads to enhanced contractility (inotropy), faster heart rate (chronotropy) and faster relaxation (lusitropy), mainly through activation of protein kinase A (PKA). Efficient enhancement of heart output under stress requires all of these responses to work together. Lusitropy is essential for shortening the heartbeat when heart rate increases. It therefore follows that, if the lusitropic response is not present, heart function under stress will be compromised. Current literature suggests that lusitropy is primarily achieved due to PKA phosphorylation of troponin I (TnI) and phospholamban (PLB). It has been well documented that PKA-induced phosphorylation of TnI releases Ca2+ from troponin C faster and increases the rate of cardiac muscle relaxation, while phosphorylation of PLB increases SERCA activity, speeding up Ca2+ removal from the cytoplasm. In this review we consider the current scientific evidences for the connection between suppression of lusitropy and cardiac dysfunction in the context of mutations in phospholamban and thin filament proteins that are associated with cardiomyopathies. We will discuss what advances have been made into understanding the physiological mechanism of lusitropy due to TnI and PLB phosphorylation and its suppression by mutations and we will evaluate the evidence whether lack of lusitropy is sufficient to cause cardiomyopathy, and under what circumstances, and consider the range of pathologies associated with loss of lusitropy. Finally, we will discuss whether suppressed lusitropy due to mutations in thin filament proteins can be therapeutically restored.

Modulation of Structure and Dynamics of Cardiac Troponin by Phosphorylation and Mutations Revealed by Molecular Dynamics Simulations

“…The phosphorylation of serines 22 and 23 of troponin I in cardiac troponin modulates the myofilbrillar Ca 2+ sensitivity and increases the rate of Ca 2+ release from troponin C. It is a major determinant of the lusitropic response to adrenergic stimulation , The molecular mechanism of this process has remained unknown long after the mechanism of the troponin Ca 2+ switch itself was defined. ,, Investigation of this subtle process at the atomic level poses a challenge for structural biology since the change in Ca 2+ sensitivity is only about twofold, and key parts of the troponin modulation and regulation system are disordered and cannot be fully resolved by most methodologies. In this study, we have used MD simulations of the cardiac troponin core to understand the molecular mechanism by which phosphorylation of serines 22 and 23 and a DCM-linked mutation, cTnC G159D, modulate Ca 2+ regulation in cardiac muscle.…”

“…Uncoupling results in a blunting of the lusitropic response to β1 receptor stimulation. 10 Since the lusitropic response is necessary for normal heart function, suppression of lusitropy by mutations can be a significant disease mechanism in cardiomyopathy. Recent high-resolution cryo-EM images of whole thin filaments at 4.8 Å resolution combined with the fitting of structures from X-ray diffraction at 2.6 Å resolution 12−15 can only partially describe muscle regulation.…”

“…Importantly, such mutations commonly affect the PKA-dependent troponin modulatory system, either mimicking the Ca 2+ -sensitivity shifts caused by phosphorylation or interfering with them such that Ca 2+ sensitivity becomes independent of phosphorylation level (uncoupling). , A well-studied example of this is the mutation in cardiac troponin C (cTnC) G159D, which causes familial DCM and has also been shown to uncouple cTnI phosphorylation from modulation of Ca 2+ sensitivity − (Figure A). Uncoupling results in a blunting of the lusitropic response to β1 receptor stimulation . Since the lusitropic response is necessary for normal heart function, suppression of lusitropy by mutations can be a significant disease mechanism in cardiomyopathy. ,, …”

“…Uncoupling results in a blunting of the lusitropic response to β1 receptor stimulation . Since the lusitropic response is necessary for normal heart function, suppression of lusitropy by mutations can be a significant disease mechanism in cardiomyopathy. ,, …”

Phospholamban R14del disease: The past, the present and the future

“…Similar lusitropic effects have also been described for another PLN mutation, namely PLN-R9C, that in heterozygote state exerts a dominant-negative effect on PLN-WT by impairing protein phosphorylation, causing chronic inhibition of SERCA2a and blunted β -adrenergic stimulation response ( 21 , 63 , 64 ). Based on the fact that loss of lusitropy has been associated with a range of DCM-associated mutations, strategies towards its restoration could have promising therapeutic potential ( 65 ).…”