Abstract
Backgrounds: Recent studies identified heterozygous variants in MYLK3 gene that encodes cardiac myosin light chain kinase (cMLCK) are related to familial dilated cardiomyopathy (DCM) for the first time. Autosomal dominant traits suggest that pathogenesis of DCM could be related to heterozygous MYLK3 loss-of-function variants (haploinsufficiency). We previously generated and examined homozygous Mylk3 knockout mice that lead to heart failure. It had yet to be examined whether heterozygous Mylk3 knockout mice represent a DCM-like phenotype.Methods and Results: Heterozygous knockout (Mylk3wild/-) mice were examined regarding cardiac function, heart histology and expression of cMLCK protein and mRNA relative to age-matched wild-type controls (Mylk3wild/wild). At 4 months of age, cardiac contractility in heterozygous knockout mice was reduced with percent fractional shortening of 23.3 ± 1.2% compared to 30.1 ± 1.8% in control (Mylk3wild/- vs. Mylk3wild/wild, n = 9 each). In 4-month-old heterozygous knockout hearts, expression of cMLCK mRNA was expectedly reduced by almost half, however, protein expression was reduced by approximately 75% relative to the control wild-type (Mylk3wild/- vs. Mylk3wild/wild, n = 9 each). Isolated ventricular cardiomyocytes from heterozygous knockout mice were larger with increase of short-axis length relative to the cardiomyocytes from control mice. However, increase of heart failure markers as well as interstitial fibrosis were not evident in heterozygous knockout mice compared to controls.Conclusion: Heterozygous Mylk3 knockout mice show mild reduction of cardiac contractility by 4 months of age, and proteins reduced by approximately 75% relative to the control wild-type mice. These mice partly resemble human with the heterozygous MYLK3 mutation, but the reduction in cardiac contractility was milder.
Highlights
The dynamics of cardiac contraction and relaxation are fundamentally related to actin-myosin interactions
There was no change in the heart weight/body weight (HW/BW) ratio between the two groups at 3 weeks of age (6.45 ± 0.16 in control vs. 6.49 ± 0.20 mg/g in heterozygous knockout mice, n = 5 and 7, respectively, P = 0.88)
We previously showed that the ubiquitin-proteasome system (UPS) is partly responsible for degrading cardiac MLCK (cMLCK) proteins in wild-type hearts and neonatal cardiomyocytes (Warren et al, 2012)
Summary
The dynamics of cardiac contraction and relaxation are fundamentally related to actin-myosin interactions. Myosin is a hexamer composed of two heavy chains and two pairs of light chains (MLC1 and MLC2). Ventricular MLC2 (MLC2v) is bound to the neck of the heavy chain, which acts as a lever arm to generate movement, and MLC2v phosphorylation has been shown to potentiate. Heterozygous Loss of Mylk Mice the rate and force of cardiac contraction (Sanbe et al, 1999; Davis et al, 2001; Moss and Fitzsimons, 2006; Stelzer et al, 2006; Scruggs and Solaro, 2011). Recent studies showed that heterozygous human mutations in MYLK3 gene could be related to familial dilated cardiomyopathy (DCM) (Tobita et al, 2017; Hodatsu et al, 2019)
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