Key result
Impairment of MYO5b expression and function, including rare missense variants identified in young patients with sudden cardiac death, promotes cardiac dysfunction, heart failure, and death.
Why the study?
The study aimed to analyse the expression patterns of class-5 myosin motor proteins in the heart, focusing on the role of MYO5b.
Does MYO5b impairment cause cardiac dysfunction, arrhythmias, and heart failure?
Does MYO5b impairment cause cardiac dysfunction, arrhythmias, and heart failure?
Impairment of MYO5b expression and function disrupts cardiac mRNA and protein trafficking, leading to arrhythmias, heart failure, and death in mice, and is associated with sudden cardiac death in humans.
MYO5b loss may promote cardiac dysfunction; hypothesis-generating for its role in human HF.
BACKGROUND AND AIMS: The present study analysed the expression patterns of class-5 myosin motor proteins (MYO5a, b, and c) in the heart with a specific focus on the role of MYO5b. METHODS: RNA-sequencing, quantitative real-time polymerase chain reaction, immunohistochemistry, Western blot, immunoprecipitation, and proteomics were performed in mice and human tissues. Functional analyses were performed in mice with a cardiac-specific knockout (KO) of MYO5b (αMHC-Cretg/-; MYO5bflox/flox), wild-type (WT) (MYO5bflox/flox), and αMHC-Cretg/- mice and in isolated adult cardiomyocytes. Next-generation sequencing screened for MYO5B gene variants in a cohort of sudden cardiac death in the young/sudden infant death syndrome patients. RESULTS: The expression of MYO5b, but not MYO5a or c, increased during postnatal cardiomyocyte maturation. Myosin-5b was reduced in end-stage failing human hearts and infarcted murine hearts. Heterozygous rare and likely pathogenic missense MYO5B gene variants (n = 6) were identified in three patients of a cohort of young patients (n = 95) who died of sudden cardiac death in the young/sudden infant death syndrome. MYO5b-KO mice revealed impaired electric conductance and metabolism, developed sarcomeric disarrangement, heart failure and death with altered mRNA levels for genes involved in sarcomere organization, fatty acid and glucose metabolism, ion channel sub-units, and Ca2+-homeostasis prior to heart failure. In cardiomyocytes, myosin-5b is associated with mitochondrial and ribosomal proteins. Myosin-5b-associated ribonucleoprotein particles (RNPs) contained mRNAs of sarcomeric, metabolic, cytoskeletal, and ion channel proteins. CONCLUSIONS: MYO5b is the major MYO5 gene expressed in postnatal cardiomyocytes where it transports vesicles, proteins, and multi-protein complexes. Among these are mRNA/RNP complexes affecting electric conductance, sarcomere homeostasis, cell metabolism, and cytoskeletal organization. Impairment in MYO5b expression and function promotes cardiac dysfunction, heart failure, and death.
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Heimerl et al. (2025) studied Sudden cardiac death in the young, sudden infant death syndrome, heart failure (n=95). MYO5b deficiency or mutation vs. Wild-type or non-failing healthy controls was evaluated on Identification of MYO5B gene variants and characterization of cardiac dysfunction. Impairment of MYO5b expression and function, including rare missense variants identified in young patients with sudden cardiac death, promotes cardiac dysfunction, heart failure, and death.
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