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

• MYL2 is sarcomeric protein and member of the EF-hand calcium-binding protein family.
• MYL2 plays an important role in embryonic heart muscle structure and function.
• In adults, MYL2 phosphorylation regulates cardiac myosin cycling kinetics, torsion and function.
• Critical phosphorylation sites include: Ser14/Ser15 in mice and Ser15 in humans.
• MLC-2v dephosphorylation has been implicated in dilated cardiomyopathy and heart failure.

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 1`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.