Heimerl Maren, Erschow Sergej, Müller-Olling Mirco, Manstein Dietmar J, Decher Niels, Kauferstein Silke, Jenewein Tina, Pich Andreas, Ricke-Hoch Melanie, Hilfiker-Kleiner Denise
Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Str. 1, Hannover 30625, Germany.
Institute for Biophysical Chemistry, Hannover Medical School, Fritz Hartmann Centre for Medical Research, Carl-Neuberg Str. 1, Hannover 30625, Germany.
Eur Heart J. 2025 Jul 1;46(25):2437-2454. doi: 10.1093/eurheartj/ehaf047.
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.
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.
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.
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.
本研究分析了5类肌球蛋白运动蛋白（MYO5a、b和c）在心脏中的表达模式，特别关注MYO5b的作用。
在小鼠和人体组织中进行了RNA测序、定量实时聚合酶链反应、免疫组织化学、蛋白质印迹、免疫沉淀和蛋白质组学分析。对心脏特异性敲除（KO）MYO5b（αMHC-CreTg/-；MYO5bflox/flox）、野生型（WT）（MYO5bflox/flox）的小鼠以及αMHC-CreTg/-小鼠和分离的成年心肌细胞进行了功能分析。下一代测序在一组年轻心脏性猝死/婴儿猝死综合征患者中筛查了MYO5B基因变异。
在出生后心肌细胞成熟过程中，MYO5b的表达增加，而MYO5a或c的表达未增加。在晚期衰竭的人类心脏和梗死的小鼠心脏中，肌球蛋白-5b减少。在一组年轻患者（n = 95）中，有3名死于年轻心脏性猝死/婴儿猝死综合征的患者被鉴定出杂合的罕见且可能致病的错义MYO5B基因变异（n = 6）。MYO5b基因敲除小鼠表现出电导和代谢受损，出现肌节排列紊乱、心力衰竭和死亡，且在心力衰竭发生前，参与肌节组织、脂肪酸和葡萄糖代谢、离子通道亚基以及钙稳态的基因的mRNA水平发生改变。在心肌细胞中，肌球蛋白-5b与线粒体和核糖体蛋白相关。与肌球蛋白-5b相关的核糖核蛋白颗粒（RNP）包含肌节、代谢、细胞骨架和离子通道蛋白的mRNA。
MYO5b是出生后心肌细胞中表达的主要MYO5基因，它在其中运输囊泡、蛋白质和多蛋白复合物。其中包括影响电导、肌节稳态、细胞代谢和细胞骨架组织的mRNA/RNP复合物。MYO5b表达和功能的损害会促进心脏功能障碍、心力衰竭和死亡。
