التفاصيل البيبلوغرافية
| العنوان: |
Dyrk1b promotes autophagy during skeletal muscle differentiation by upregulating 4e-bp1. |
| المؤلفون: |
Bhat, Neha1 (AUTHOR), Narayanan, Anand1 (AUTHOR), Fathzadeh, Mohsen1 (AUTHOR), Shah, Kanan1 (AUTHOR), Dianatpour, Mehdi2,3 (AUTHOR), Abou Ziki, Maen D.1 (AUTHOR), Mani, Arya1,4 (AUTHOR) arya.mani@yale.edu |
| المصدر: |
Cellular Signalling. Feb2022, Vol. 90, pN.PAG-N.PAG. 1p. |
| مصطلحات موضوعية: |
*SKELETAL muscle, *GAIN-of-function mutations, *AUTOPHAGY, *MUSCLE growth, *GENE regulatory networks, *PROTEIN kinases |
| مستخلص: |
Rare gain of function mutations in the gene encoding Dyrk1b, a key regulator of skeletal muscle differentiation, have been associated with sarcopenic obesity (SO) and metabolic syndrome (MetS) in humans. So far, the global gene networks regulated by Dyrk1b during myofiber differentiation have remained elusive. Here, we have performed untargeted proteomics to determine Dyrk1b-dependent gene-network in differentiated C2C12 myofibers. This analysis led to identification of translational inhibitor, 4e-bp1 as a post-transcriptional target of Dyrk1b in C2C12 cells. Accordingly, CRISPR/Cas9 mediated knockout of Dyrk1b in zebrafish identified 4e-bp1 as a downstream target of Dyrk1b in-vivo. The Dyrk1b knockout zebrafish embryos exhibited markedly reduced myosin heavy chain 1 expression in poorly developed myotomes and were embryonic lethal. Using knockdown and overexpression approaches in C2C12 cells, we found that 4e-bp1 enhances autophagy and mediates the effects of Dyrk1b on skeletal muscle differentiation. Dyrk1bR102C, the human sarcopenic obesity-associated mutation impaired muscle differentiation via excessive activation of 4e-bp1/autophagy axis in C2C12 cells. Strikingly, the defective muscle differentiation in Dyrk1bR102C cells was rescued by reduction of autophagic flux. The identification of Dyrk1b-4e-bp1-autophagy axis provides significant insight into pathways that are relevant to human skeletal muscle development and disorders. • 4e-bp1 is an evolutionary conserved target of Dyrk1b and a critical role in in skeletal muscle differentiation in-vitro. • Dyrk1b increases the stability of 4e-bp1 protein in a kinase independent manner. • Dyrk1b increases basal autophagic flux in-vitro. • The human metabolic syndrome- and sarcopenic obesity-linked Dyrk1bR102C has a gain of function effect on autophagy. [ABSTRACT FROM AUTHOR] |
| قاعدة البيانات: |
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