MYL2

Myosin regulatory light chain 2, ventricular/cardiac muscle isoform (MLC-2) also known as the regulatory light chain of myosin (RLC) is a protein that in humans is encoded by the MYL2 gene.^[5][6] This cardiac ventricular RLC isoform is distinct from that expressed in skeletal muscle (MYLPF), smooth muscle (MYL12B) and cardiac atrial muscle (MYL7).^[7]

Ventricular myosin light chain-2 (MLC-2v) refers to the ventricular cardiac muscle form of myosin light chain 2 (Myl2). MLC-2v is a 19-KDa protein composed of 166 amino acids, that belongs to the

MLC-2v plays an essential role in early embryonic cardiac development and function.[25] and represents one of the earliest markers of ventricular specification.^[26] During early development (E7.5-8.0), MLC-2v is expressed within the cardiac crescent. The expression pattern of MLC-2v becomes restricted to the ventricular segment of the linear heart tube at E8.0 and remains restricted within the ventricle into adulthood.^[26][27]

Phosphorylation sites and regulators

Recent studies have highlighted a critical role for MLC2v phosphorylation in cardiac torsion, function and disease.^[28] In cardiac muscle, the critical phosphorylation sites have been identified as Ser14/Ser15 in the mouse heart and Ser15 in the human heart.^[29] The major kinase responsible for MLC-2v phosphorylation has been identified as cardiac myosin light chain kinase (MLCK), encoded for by Mylk3.^[29][30] Loss of cardiac MLCK in mice results in loss of cardiac MLC-2v phosphorylation and cardiac abnormalities.^[24][31]

Clinical significance

Mutations in MYL2 have been associated with familial hypertrophic cardiomyopathy (FHC). Ten FHC mutations have been identified in RLC: E22K, A13T, N47K, P95A, F18L, R58Q, IVS6-1G>C, L103E, IVS5-2A>G, D166V. The first three-E22K, A13T and N47K-have been associated with an unusual mid-ventricular chamber obstruction type of hypertrophy.^[32][33] Three mutations-R58Q, D166V and IVS5-2-are associated with more malignant outcomes, manifesting with sudden cardiac death or at earlier ages.^{[34][35][36][37]} Functional studies demonstrate that FHC mutations in RLC affect its ability to both be phosphorylated and to bind calcium/magnesium.^[38]

Effects on cardiac muscle contraction

MLC-2v plays an important role in cross-bridge cycling kinetics and cardiac muscle contraction.^[39] MLC-2v phosphorylation at Ser14 and Ser15 increases myosin lever arm stiffness and promotes myosin head diffusion, which altogether slow down myosin kinetics and prolong the duty cycle as a means to fine-tune myofilament Ca2+ sensitivity to force.^[39]

Effects on adult cardiac torsion, function and disease

A gradient in the levels of both MLC2v phosphorylation and its kinase, cardiac MLCK, has been shown to exist across the human heart from endocardium (low phosphorylation) to epicardium (high phosphorylation).^[40] The existence of this gradient has been proposed to impact cardiac torsion due to the relative spatial orientation of endocardial versus epicardial myofibers.^[40] In support of this, recent studies have shown that MLC-2v phosphorylation is critical in regulating left ventricular torsion.^[31][39] Variations in myosin cycling kinetics and contractile properties as a result of differential MLC-2v phosphorylation (Ser14/15) influence both epicardial and endocardial myofiber tension development and recovery to control cardiac torsion and myofiber strain mechanics.^[31][39]

A number of human studies have implicated loss of MLC-2v phosphorylation in the pathogenesis of human dilated cardiomyopathy and heart failure.^{[29][41][42][43][44]} MLC-2v dephosphorylation has also been reported in human patients carrying a rare form of familial hypertrophic cardiomyopathy (FHC) based on specific MLC-2v and MLCK mutations.^[16][40][45]

Animal studies

MLC-2v plays a key role in the regulation of cardiac muscle contraction, through its interactions with myosin.^[28] Loss of MLC-2v in mice is associated with ultrastructural defects in sarcomere assembly and results in dilated cardiomyopathy and heart failure with reduced ejection fraction, leading to embryonic lethality at E12.5.^[25] More recently, a mutation in zebrafish tell tale heart (telm225) that encodes MLC-2, demonstrated that cardiac MLC-2 is required for thick filament stabilization and contractility in the embryonic zebrafish heart.^[46]

The role of Myl2 mutations in pathogenesis has been determined through the generation of a number of mouse models.^[39][47][48] Transgenic mice overexpressing the human MLC-2v R58Q mutation, which is associated with FHC has been shown to lead to a reduction in MLC-2v phosphorylation in hearts.^[47] These mice exhibited features of FHC, including diastolic dysfunction that progressed with age.^[47] Similarly, cardiac overexpression of another FHC-associated MLC-2v mutation (D166V) results in loss of MLC-2v phosphorylation in mouse hearts.^[48] In addition to these findings, MLC-2v dephosphorylation in mice results in cardiac dilatation and dysfunction associated with features reminiscent of dilated cardiomyopathy, leading to heart failure and premature death.^[18][31][39] Altogether these studies highlight a role for MLC-2v phosphorylation in adult heart function. These studies also suggest that torsion defects might be an early manifestation of dilated cardiomyopathy consequent to loss of MLC-2v phosphorylation.^[39] MLC-2v also plays an important role in cardiac stress associated with hypertrophy.^[31][39] In a novel MLC2v Ser14Ala/Ser15Ala knockin mouse model, complete loss of MLC2v (Ser14/Ser15) phosphorylation led to a worsened and differential (eccentric as opposed to concentric) response to pressure overload-induced hypertrophy.^[39] In addition, mice lacking cardiac MLCK display heart failure and experience premature death in response to both pressure overload and swimming induced hypertrophy.^[31] Consistent with these findings, a cardiac-specific transgenic mouse model overexpressing cardiac MLCK attenuated the response to cardiac hypertrophy induced by pressure overload.^[31] Furthermore, in a cardiac-specific transgenic mouse model overexpressing skeletal myosin light chain kinase, the response to cardiac hypertrophy induced by treadmill exercise or isoproterenol was also attenuated.^[49] These studies further highlight the therapeutic potential of increasing MLC-2v phosphorylation in settings of cardiac pathological stress.

Notes

References