Deficiency in nebulin repeats of sarcomeric nebulette is detrimental for cardiomyocyte tolerance to exercise and biomechanical stress.
Deficiency in nebulin repeats of sarcomeric nebulette is detrimental for cardiomyocyte tolerance to exercise and biomechanical stress.
复制标题
肌节星云的星云蛋白重复序列的缺乏不利于心肌细胞对运动和生物力学应激的耐受性。
DOI：
10.1152/ajpheart.00732.2020
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Purevjav,Enkhsaikhan
中科院分区：
文献类型：
--
作者：
Vejandla,RamonaM;Orgil,Buyan-Ochir;Alberson,NeelyR;Li,Ning;Munkhsaikhan,Undral;Khuchua,Zaza;Martherus,Ruben;Azeloglu,EvrenU;Xu,Fuyi;Lu,Lu;Towbin,JeffreyA;Purevjav,Enkhsaikhan
The actin-binding sarcomeric nebulette (NEBL) protein provides efficient contractile flexibility via interaction with desmin intermediate filaments.NEBLgene mutations affecting the nebulin repeat (NR) domain are known to induce cardiomyopathy. The study aimed to explore the roles of NEBL in exercise and biomechanical stress response. We ablated exon3 encoding the first NR ofNebland created global Neblex3-/ex3-knockout mice. Cardiac function, structure, and transcriptome were assessed before and after a 4-wk treadmill regimen. ANebl-based exercise signaling network was constructed using systems genetics methods. H9C2 and neonatal rat cardiomyocytes (NRCs) expressing wild-type or mutant NEBL underwent cyclic mechanical strain. Neblex3-/ex3-mice demonstrated diastolic dysfunction with preserved systolic function at 6 mo of age. After treadmill running, 4-mo-old Neblex3-/ex3-mice developed concentric cardiac hypertrophy and left ventricular dilation compared with running Nebl+/+and sedentary Neblex3-/ex3-mice. Disturbance of sarcomeric Z-disks and thin filaments architecture and disruption of intercalated disks and mitochondria were found in exercised Neblex3-/ex3-mice. ANebl-based exercise signaling network includedCsrp3,Des,Fbox32,Jup,Myh6, andMyh7. Disturbed expression of TM1, DES, JUP, β-catenin, MLP, α-actinin2, and vinculin proteins was demonstrated. In H9C2 cells, NEBL was recruited into focal adhesions at 24-h poststrain and redistributed along with F-actin at 72-h poststrain, suggesting time-dependent redistribution of NEBL in response to strain.NEBLmutations cause desmin disorganization in NRCs upon stretch. We conclude that Nebl's NR ablation causes disturbed sarcomere, Z-disks, and desmin organization, and prevents NEBL redistribution to focal adhesions in cardiomyocytes, weakening cardiac tolerance to biomechanical stress.NEW & NOTEWORTHYWe demonstrate that ablation of first nebulin-repeats of sarcomeric nebulette (Nebl) causes diastolic dysfunction in Neblex3-/ex3-mice. Exercise-induced development of diastolic dysfunction, cardiac hypertrophy and ventricular dilation in knockouts. This was associated with sarcomere disturbance, intercalated disks disruption, and mitochondrial distortion upon stress and altered expression of genes involved inNebl-based stress network. We demonstrate that G202R and A592 mutations alter actin and desmin expression causing disorganization of desmin filaments upon cyclic strain.
