The Slow Cardiac Myosin Regulatory Light Chain in Heart Failure

Contraction in striated muscle relies on myofibrils.The myofibrils consist of thick filaments and thin filaments that slide past each other during sarcomere shortening and lengthening.The thick filament is composed principally of myosin, and also includes titin and myosin binding protein C. Myosin in turn is composed of several constituent proteins.1 Myosin is a hexameric contractile protein with ATPase activity.The myosin molecule is a ''molecular motor.''It converts adenosine triphosphate energy into directional movement.It consists of 2 heavy chains, 2 ''essential'' light chains, and 2 ''regulatory'' light chains (Figure 1).The essential light chains are nonphosphorylated, whereas the regulatory light chains undergo phosphorylation and dephosphorylation.The regulatory light chain that is expressed in slow cardiac muscle is termed the slow cardiac myosin regulatory light chain (MYL2).It is encoded by the MYL2 gene.In contrast, the myosin regulatory light chain expressed in fast skeletal muscle is encoded by the MYL1 gene.The MYL3 gene encodes the essential light chains.In the current issue of Clinical Cardiology, Li et al report on down-expression of the MYL2 gene in chronic heart failure patients.2 The slow cardiac myosin regulatory light chain was studied in tissue sections using immunohistochemistry.In addition, analyses were confirmed in vitro using western blot techniques.Interestingly, there is downregulation of MYL2 in patients identified as having moderate heart failure.There is still further down-regulation in patients identified as having severe heart failure.Patients included in the study had clinical evidence of valvular cardiomyopathy, dilated cardiomyopathy, or hypertrophic cardiomyopathy.The data were normalized against beta actin.Because beta actin is present only in thin filaments, it is not entirely clear whether the MYL2 gene was preferentially down-regulated, or whether all thick-filament proteins were down-regulated.Because the data were not normalized against a thick-filament protein, this cannot be ascertained from the present study.The data presented are provocative.They suggest an association between down-regulation of MYL2 and the severity of the clinical heart failure.This is interesting in light of recent studies on the kinases that are capable of phosphorylating this protein.Cardiac myosin light chain kinase (cMLCK) is encoded by the cMLCK gene and is a protein approximately 90 kDa in size.This protein is activated by calcium and calmodulin.In mouse studies the cMLCK protein phosphorylates, and thereby regulates, MYL2.Mice in which cMLCK gene expression is ablated have profound cardiac hypertrophy and fibrosis.3 The author has no funding, financial relationships, or conflicts of interest to disclose.