Cardiac dysfunction related to cardiac mRNA and protein traffic impairment due to reduced unconventional motor protein myosin-5b expression

被引:2
作者
Heimerl, Maren [1 ]
Erschow, Sergej [1 ]
Mueller-Olling, Mirco [1 ]
Manstein, Dietmar J. [2 ,3 ]
Decher, Niels [4 ,5 ]
Kauferstein, Silke [6 ,7 ]
Jenewein, Tina [6 ]
Pich, Andreas [8 ]
Ricke-Hoch, Melanie [1 ]
Hilfiker-Kleiner, Denise [1 ,9 ]
机构
[1] Hannover Med Sch, Dept Cardiol & Angiol, Carl Neuberg Str 1, D-30625 Hannover, Germany
[2] Hannover Med Sch, Inst Biophys Chem, Fritz Hartmann Ctr Med Res, Carl Neuberg Str 1, D-30625 Hannover, Germany
[3] Hannover Med Sch, Div Struct Biochem, Carl Neuberg Str 1, D-30625 Hannover, Germany
[4] Philipps Univ Marburg, Med Fac, Dept Vegetat Physiol, Deutschausstr 1-2, D-35037 Marburg, Germany
[5] Philipps Univ Marburg, Med Fac, Ctr Mind Brain & Behav CMBB, Deutschausstr 1-2, D-35037 Marburg, Germany
[6] Goethe Univ Frankfurt, Univ Hosp, Inst Legal Med, Kennedyallee 104, D-60598 Frankfurt, Germany
[7] German Ctr Cardiovasc Res, Deutsch Zentrum Herz Kreislauf Forsch DZHK, Partner Site Rhein Main, D-60598 Frankfurt, Germany
[8] Hannover Med Sch, Inst Toxicol, Core Facil Prote, Carl Neuberg Str 1, D-30625 Hannover, Germany
[9] Phillipps Univ Marburg, Dept Cardiovasc Complicat Oncol Therapies, Med Fac, Baldingerstr, D-35032 Marburg, Germany
关键词
Class-5 myosin motor proteins MYO5a and MYO5b; Heart failure; Arrhythmias; Sarcomere; Ribosomes; RNA trafficking; HEAVY-CHAIN; DEVELOPMENTAL EXPRESSION; POTASSIUM CHANNELS; INCLUSION DISEASE; GENE; CARDIOMYOPATHY; LOCALIZATION; EXOCYTOSIS; MUTATIONS; TRANSPORT;
D O I
10.1093/eurheartj/ehaf047
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 (alpha MHC-Cretg/-; MYO5bflox/flox), wild-type (WT) (MYO5bflox/flox), and alpha MHC-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.
引用
收藏
页码:2437 / 2454
页数:18
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