Abstract
Sex disparities modulate cardiac function, although the proteins and mechanisms remain to be elucidated. We recently demonstrated a mosaic pattern of protein expression in the heart for over 100 proteins. Here we investigate one of these proteins, myosin light chain 4 (MYL4), which is important for contractile functions by increasing force production. We assayed the expression pattern of MYL4 across 756 ventricular myocardial samples from 668 individuals utilizing a semi-automated Cell Profiler method on five tissue microarrays (TMAs) of cardiac tissues across a diverse set of diseases. The percentage of MYL4 positive cells was significantly higher in male subjects independently across all five TMAs, regardless of disease state (p = 8.66e-15). Higher MYL4 expression was also modestly associated with hypertrophic cardiomyopathy (p = 6.3e-04). MYL4 expression did not associate with sudden cardiac death or other cardiomyopathies. This study demonstrates a new mosaic pattern of protein expression that underlies sex disparities in the human heart.
Highlights
Sex disparities in cardiac function have long been recognized
myosin light chain 4 (MYL4) expression is significantly increased in patients with hypertrophic cardiomyopathy (HCM)[14], ischemic heart disease (IHD)[15], and dilated cardiomyopathy (DCM)[15]
Increased MYL4 expression has even been found in congenital heart diseases such as Tetralogy of Fallot (TOF), double outlet right ventricle (DORV), and infundibular pulmonary stenosis (IPS)[17]
Summary
Sex disparities in cardiac function have long been recognized. These have been identified at the level of Ca2+ handling with differences in protein levels, contraction times, relaxation times, and myofilament responsiveness[1,2,3]. Sex hormones have been implicated in regulating cardiac natriuretic hormones and modulating cardiac fibrosis[5,6] The summation of these effects are disparities in clinical outcomes between men and women including higher rates of female mortality in congestive heart failure[7]. In a second study of gene expression differences by sex in human dilated cardiomyopathy, MYH7 was 2.5 fold increased in women and myosin light chain 4 (MYL4) was 1.7 fold decreased[9]. Consistent with established literature, MYL4 expression is robust and homogeneous in the atria It is universally present in fetal and neonatal ventricular tissues. From infancy until roughly 5 years of age, the percent of ventricular cardiomyocytes expressing MYL4 decreases from 100% to roughly 15%, causing a mosaic pattern of expression. Upregulation may be a general marker of cardiac stress or a structural change with a need to improve contractile function
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