Cardiomyopathic mutations in essential light chain reveal mechanisms regulating the super relaxed state of myosin

In this study, we assessed the super relaxed (SRX) state of myosin and sarcomeric protein phosphorylation in two pathological models of cardiomyopathy and in a near-physiological model of cardiac hypertrophy. The cardiomyopathy models differ in disease progression and severity and express the hypertrophic (HCM-A57G) or restrictive (RCM-E143K) mutations in the human ventricular myosin essential light chain (ELC), which is encoded by the MYL3 gene. Their effects were compared with near-physiological heart remodeling, represented by the N-terminally truncated ELC (Δ43 ELC mice), and with nonmutated human ventricular WT-ELC mice. The HCM-A57G and RCM-E143K mutations had antagonistic effects on the ATP-dependent myosin energetic states, with HCM-A57G cross-bridges fostering the disordered relaxed (DRX) state and the RCM-E143K model favoring the energy-conserving SRX state. The HCM-A57G model promoted the switch from the SRX to DRX state and showed an ∼40% increase in myosin regulatory light chain (RLC) phosphorylation compared with the RLC of normal WT-ELC myocardium. On the contrary, the RCM-E143K–associated stabilization of the SRX state was accompanied by an approximately twofold lower level of myosin RLC phosphorylation compared with the RLC of WT-ELC. Upregulation of RLC phosphorylation was also observed in Δ43 versus WT-ELC hearts, and the Δ43 myosin favored the energy-saving SRX conformation. The two disease variants also differently affected the duration of force transients, with shorter (HCM-A57G) or longer (RCM-E143K) transients measured in electrically stimulated papillary muscles from these pathological models, while no changes were displayed by Δ43 fibers. We propose that the N terminus of ELC (N-ELC), which is missing in the hearts of Δ43 mice, works as an energetic switch promoting the SRX-to-DRX transition and contributing to the regulation of myosin RLC phosphorylation in full-length ELC mice by facilitating or sterically blocking RLC phosphorylation in HCM-A57G and RCM-E143K hearts, respectively.

Elevated Intraoperative Expression of Ventricular Myosin Light Chain Predicts Heart Failure after Valve Replacement Surgery

<p><b>Background:</b> It can be difficult to predict which patients will survive and recover cardiac function after valve replacement surgery. We hypothesized that the expression levels of ventricular myosin light chain (MLCv) might reflect the severity of disease or the extent of irreversible myocardial damage and might be useful for predicting the postoperative course. Thus, the aim of this study was to explore the relationship between MLCv expression in specimens obtained during valve replacement surgery and the postoperative New York Heart Association (NYHA) class.</p><p><b>Methods:</b> The levels of expression of the regulatory MLCv (MLC-2v) and MLC-1v in papillary muscle specimens from 80 patients who underwent valve replacement surgery for rheumatic valvular disease were evaluated by Western blot analysis.</p><p><b>Results:</b> The patients were similar with regard to the intraoperative expression of MLC-1v, regardless of postoperative NYHA class. The preoperative NYHA class, the end-systolic left ventricular internal dimension, and the intraoperative expression of MLC-2v emerged as independent risks factors for a NYHA class status of III/IV at 6 months after surgery, with an area under the receiver operating characteristic curve of 0.862.</p><p><b>Conclusion:</b> The intraoperative level of MLC-2v expression was predictive of the patients' NYHA class after valve replacement surgery. This result suggests that future studies evaluating the use of preoperative specimens (such as biopsy or peripheral blood samples) for measurement of MLC-2v levels could lead to a valuable preoperative tool for the assessment of candidates for valve replacement.</p>