Abstract
In skeletal muscle, myoblast differentiation results in the formation of multinucleated myofibers. Although recent studies have shown that unfolded protein responses (UPRs) play an important role in intracellular remodeling and contribute to skeletal muscle differentiation, the involvement of IRE1–XBP1 signaling, a major UPR signaling pathway, remains unclear. This study aimed to investigate the effect of the IRE1–XBP1 pathway on skeletal muscle differentiation. In C2C12 cells, knockdown of IRE1 and XBP1 in cells remarkably suppressed differentiation. In addition, apoptosis and autophagy were dramatically enhanced in the XBP1-knockdown cells, highlighting the participation of IRE1–XBP1 in cell survival maintenance with differentiation stimuli during skeletal muscle differentiation. In myogenic cells, we demonstrated that the expression of CDK5 (cyclin-dependent kinase 5) is regulated by XBP1s, and we propose that XBP1 regulates the expression of MyoD family genes via the induction of CDK5. In conclusion, this study revealed that IRE1–XBP1 signaling plays critical roles in cell viability and the expression of differentiation-related genes in predifferentiated myoblasts and during the early differentiation phase.
Highlights
Skeletal muscle tissue is constituted by multinucleated myofibers formed as a result of mononuclear myoblasts fused to each other
We found that C2C12 mouse skeletal muscle cells overexpressing the P56S-missense mutated vesicle-associated membrane protein/synaptobrevin-associated membrane protein (VAPB), which is the causative gene of familial amyotrophic lateral sclerosis (ALS) [29], exhibit marked myotube formation disruption and IRE1 activation inhibition [30]; this suggests that IRE1
Our current study demonstrates that the unfolded protein responses (UPRs) factors IRE1 and XBP1s are indispensable for myogenic differentiation
Summary
Skeletal muscle tissue is constituted by multinucleated myofibers formed as a result of mononuclear myoblasts fused to each other. Myogenic differentiation is divided into several different stages [1]. In their mononuclear stages, MyoD and Myf are involved in the determination of myoblasts, maintenance of cell proliferation, and induction of subsequent gene expression [2,3]. The myoblasts undergo cell cycle arrest, and the gene expression of myogenin and Mef2c is induced, leading to myoblast cell fusion and terminal differentiation [4,5]. Previous studies have identified factors and signaling pathways essential for the late stage of myogenic differentiation to control cell fusion, myofiber formation, and terminal differentiation, the early stage just before and after initial differentiation remains to be characterized
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