Functions of myosin light chain-2 (MYL2) in cardiac muscle and disease

Abstract

Myosin light chain-2 (MYL2, also called MLC-2) is an ∼19 kDa sarcomeric protein that belongs to the EF-hand calcium binding protein superfamily and exists as three major isoforms encoded by three distinct genes in mammalian striated muscle. Each of the three different MLC-2 genes (MLC-2f; fast twitch skeletal isoform, MLC-2v; cardiac ventricular and slow twitch skeletal isoform, MLC-2a; cardiac atrial isoform) has a distinct developmental expression pattern in mammals. Genetic loss-of-function studies in mice demonstrated an essential role for cardiac isoforms of MLC-2, MLC-2v and MLC-2a, in cardiac contractile function during early embryogenesis. In the adult heart, MLC-2v function is regulated by phosphorylation, which displays a specific expression pattern (high in epicardium and low in endocardium) across the heart. These data along with new data from computational models, genetic mouse models, and human studies have revealed a direct role for MLC-2v phosphorylation in cross-bridge cycling kinetics, calcium-dependent cardiac muscle contraction, cardiac torsion, cardiac function and various cardiac diseases. This review focuses on the regulatory functions of MLC-2 in the embryonic and adult heart, with an emphasis on phosphorylation-driven actions of MLC-2v in adult cardiac muscle, which provide new insights into mechanisms regulating myosin cycling kinetics and human cardiac diseases.

Distinct sequences and post-translational modifications in cardiac atrial and ventricular myosin light chains revealed by top-down mass spectrometry

“…Four of these genes are expressed in the heart, with expression patterns that vary by chamber, developmentally, and in response to pathological stimuli [7, 10, 15]. The MYL3 and MYL4 genes encode the ventricular (ELC v ) and atrial (ELC a ) isoforms of the ELC, while the ventricular (RLC v ) and atrial (RLC a ) isoforms of the RLC are encoded by the MYL2 and MYL7 genes, respectively.…”

“…In adulthood, however, expression of the ELC a is restricted to the atria, although re-expression in the ventricles occurs in response to pressure overload and heart failure [7, 10, 21]. On the other hand, RLC v expression is restricted to the ventricles both in the developing and adult heart [15]. Conversely, RLC a , like ELC a , is expressed throughout the heart early in development, and becomes restricted to the atria later in development [15].…”

Cardiac myosin light chain is phosphorylated by Ca 2+ /calmodulin-dependent and -independent kinase activities

“…In addition, overexpression of an RLC phosphomimetic mutation S15D in the background of a hypertrophic cardiomyopathy-associated mutation D166V was recently shown to prevent the development of a disease phenotype associated with the overexpression of D166V mutant RLC (28). Although animal studies have solidified the requirement of RLC S15 phosphorylation for normal cardiac performance (29), and have confirmed that cMLCK is the primary protein kinase responsible for phosphorylation of RLC in ventricular muscle, information on the regulation of RLC phosphorylation and the enzymatic properties of cMLCK is conflicting (8,9). In addition, residual RLC phosphorylation (20-25% of normal RLC phosphorylation) in cMLCK-KO animals indicates that another MLCK could phosphorylate RLC.…”

Phosphorylation of the regulatory light chain of myosin in striated muscle: methodological perspectives

“…In the heart, genetic knock-out mice were used to understand the role of the ventricular and atrial isoforms of RLC, MYL2v, and MYL2a, respectively, in cardiac contractile function (Sheikh et al 2015). The mutations of RLC are associated with the mid left ventricular chamber hypertrophic cardiomyopathy (HCM) phenotype.…”