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.

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Figure 1. Schematic diagram of the myosin molecule. The head region contains the actin binding regions and the ATP binding sites. The hinge region is stabilized by essential light chain proteins and regulatory light chain proteins. The myosin rod region then extends outward. Abbreviations: ATP, adenosine triphosphate.

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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 down-regulation 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 When evaluated echocardiographically, these mice show increased ventricular mass and increased end-diastolic ventricular dimensions when the ability to phosphorylate MYL2 is absent.3 This suggests an important regulatory function of phosphorylation and dephosphorylation for the integrity of the cardiac muscle cell. Furthermore, microarray studies looking across the entire genome have also implicated myosin light chain kinases as being associated with the pulmonary arterial hypertension that is associated with left ventricular dysfunction.4

Taken together, the available data provide a tantalizing association between dysregulation of MYL2 and clinical features of progressive cardiomyopathy and heart failure. The fact that this association is seen across mouse-model systems, human clinical studies, and gene-expression profile arrays suggests that this is a potentially important mechanistic pathway rather than simply an association without cause and effect. It is easy to speculate that dysregulation of calcium/calmodulin, phosphorylation/dephosphorylation, or generalized down-regulation of MYL2 gene expression could all play a molecular role in a final common cardiomyopathy pathway. Through this type of molecular dysregulation, valvular heart disease, genetic cardiomyopathies, and acquired nonischemic cardiomyopathies may all funnel into the same common highway leading to apoptosis, myocyte dropout, and progressive dysfunction.


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  2. References
  • 1
    Palmer BM. Thick filament proteins and performance in human heart failure. Heart Fail Rev. 2005;10:187197.
  • 2
    Li Y, Gang W, Qizhu T, et al. Slow cardiac myosin regulatory light chain 2 (myl2) was down-expressed in chronic heart failure patients. Clin Cardiol. 2010;33:3034.
  • 3
    Ding P, Huang J, Battiprolu PK, et al. Cardiac myosin light chain kinase is necessary for myosin regulatory light chain phosphorylation and cardiac performance in vivo. J Biol Chem. 2010 doi:10.1074/jbc.M110.160499.
  • 4
    Min KD, Asakura M, Liao Y, et al. Identification of genes related to heart failure using global gene expression profiling of human failing myocardium. Biochem Biophys Res Commun. 2010;393:5560.