NDRG4 promotes myogenesis via Akt/CREB activation.

Mingfei Zhu,Rong Zheng,Yiwen Guo,Yunxia Zhang,Bo Zuo

doi:10.18632/oncotarget.21591

Abstract

N-Myc downstream-regulated gene 4 (NDRG4) plays an important role in biological processes and pathogenesis, but its function in muscle development is unclear. In this study, we investigated the function of the NDRG4 gene in the regulation of myogenic differentiation. NDRG4 expression is upregulated during muscle regeneration and C2C12 myoblast differentiation. Gain and loss of function studies revealed that NDRG4 dramatically promotes expression of myogenic differentiation factor (MyoD), myogenin (MyoG), and myosin heavy chain (MyHC) genes and myotube formation. Mechanistically, the binding of NDRG4 to carboxyl-terminal modulator protein (CTMP) abates the interaction of CTMP and protein kinase B (Akt) and increases the phosphorylation of Akt and cAMP response element binding protein (CREB), which leads to increased expression of myogenic genes. Our results reveal that NDRG4 promotes myogenic differentiation via Akt/CREB activation.

Highlights

Muscle formation is a well-orchestrated process in which pluripotent mesodermal cells give rise to myoblasts, subsequently proliferate, withdraw from the cell cycle, and differentiate into myotubes [1]
Western blotting results indicated that www.impactjournals.com/oncotarget the N-Myc downstream-regulated gene 4 (NDRG4) protein was detected in proliferating myoblasts and that expression increased during myogenic differentiation, while the protein expression levels of two myogenic marker genes (MyoG and myosin heavy chain (MyHC)) increased greatly during myogenic differentiation of C2C12 cells (Figure 1B)
As myogenic differentiation is an important event during skeletal muscle regeneration, we investigated the change in NDRG4 mRNA expression following CTX-mediated injury of mouse skeletal muscle

Summary

Introduction

Muscle formation is a well-orchestrated process in which pluripotent mesodermal cells give rise to myoblasts, subsequently proliferate, withdraw from the cell cycle, and differentiate into myotubes [1]. Myf and MyoD are primary MRF proteins expressed at the myoblast stage and are essential for skeletal muscle lineage determination [4]. MyoD overexpression alone is sufficient to reprogram fibroblasts into muscle cells [5, 6]. Downregulation of MyoG can even reverse terminal muscle cell differentiation [7]. The activity of such factors is under tight posttranslational control by signal transduction pathways, including the Akt pathway [8]. CREB is the downstream molecule of Akt and plays important roles in the differentiation of muscle cells [12,13,14,15]. The Akt/CREB signaling pathway is critical for muscle development and involves multiple proteins and molecules

Methods

Results

Conclusion