ALS-Linked P56S-VAPB Mutation Impairs the Formation of Multinuclear Myotube in C2C12 Cells

Tokutake, Yukako; Yamada, Keita; Ohata, Masaki; Obayashi, Yoshihito; Tsuchiya, Megumi; Yonekura, Shinichi

doi:10.3390/ijms160818628

Cited by 20 publications

(21 citation statements)

References 36 publications

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“…Moreover, the IRE1a-dependent pathway was impaired in C2C12 cells transfected with mutant VAPB, which is a cause of familial ALS involved in vesicle trafficking. This occurred in association with a limited capacity to form myotubes, thus suggesting that the dysfunction of the unfolded protein response might interfere with the maintenance of muscle integrity in ALS (115).…”

Section: Multiple Pathways Lead To Als Muscle Degenerationmentioning

confidence: 99%

The Role of Skeletal Muscle in Amyotrophic Lateral Sclerosis

et al. 2016

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Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset disease primarily characterized by upper and lower motor neuron degeneration, muscle wasting and paralysis. It is increasingly accepted that the pathological process leading to ALS is the result of multiple disease mechanisms that operate within motor neurons and other cell types both inside and outside the central nervous system. The implication of skeletal muscle has been the subject of a number of studies conducted on patients and related animal models. In this review, we describe the features of ALS muscle pathology and discuss on the contribution of muscle to the pathological process. We also give an overview of the therapeutic strategies proposed to alleviate muscle pathology or to deliver curative agents to motor neurons. ALS muscle mainly suffers from oxidative stress, mitochondrial dysfunction and bioenergetic disturbances. However, the way by which the disease affects different types of myofibers depends on their contractile and metabolic features. Although the implication of muscle in nourishing the degenerative process is still debated, there is compelling evidence suggesting that it may play a critical role. Detailed understanding of the muscle pathology in ALS could, therefore, lead to the identification of new therapeutic targets.

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Section: Multiple Pathways Lead To Als Muscle Degenerationmentioning

confidence: 99%

The Role of Skeletal Muscle in Amyotrophic Lateral Sclerosis

et al. 2016

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“…Quantitative analyses were performed as described previously using ImageJ software from the NIH (Tokutake et al, ). C2C12 cells that had been immunostained for myosin heavy‐chain (MHC) and stained with DAPI were analyzed quantitatively.…”

Section: Methodsmentioning

confidence: 99%

Thermal stimulation at 39°C facilitates the fusion and elongation of C2C12 myoblasts

Hayashi

Yonekura

2019

Animal Science Journal

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The aim of this study was to determine the effect of thermal stimulation at 39°C on the fusion and elongation of skeletal muscle cells. During a 5 day differentiation process of C2C12 cells, nine groups subjected to varying lengths of thermal stimulation at 39°C were established. Afterward, all groups were immunostained using antimuscle heavy-chain antibody to test for myotube formation. Quantification of the myotube area demonstrated a significant increase in the group subjected to thermal stimulation at 39°C during the latter half of the differentiation compared with the control group, but the fusion index was significantly higher in the group that received hyperthermic treatment during the first half of the differentiation period. Moreover, the longitudinal length of myotubes was significantly increased in the groups that were subjected to thermal stimulation at 39°C during the latter half of the differentiation period. The distance between the center of myotubes and the nucleus farthest away from the center was substantially extended in the group receiving thermal stimulation at 39°C only on the fourth day of the differentiation. Together, these results demonstrate that thermal stimulation at 39°C facilitates myoblast fusion and elongation. K E Y W O R D Sdifferentiation, fusion, mild heat stress, myotube, nuclear migration

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“…C2C12 mouse myoblasts were obtained from DS Pharma Biomedical (Osaka, Japan). The cells were cultured as described previously [30]. Briefly, the cells were cultured in growth medium (DMEM/FBS 10%) under 5% CO 2 at 37 • C; differentiation was induced by changing the medium (DMEM/HS 2%) once the cells reached confluency.…”

Section: Cell Culturementioning

confidence: 99%

“…In a previous study, 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 positively controls myogenic differentiation as well as other UPR-sensor factors. Acosta et al reported that overexpression of spliced XBP1 suppresses C2C12 myogenic differentiation [31].…”

Section: Introductionmentioning

confidence: 99%

IRE1-XBP1 Pathway of the Unfolded Protein Response Is Required during Early Differentiation of C2C12 Myoblasts

Tokutake

Yamada

Hayashi

et al. 2019

IJMS

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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.

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ALS-Linked P56S-VAPB Mutation Impairs the Formation of Multinuclear Myotube in C2C12 Cells

Cited by 20 publications

References 36 publications

The Role of Skeletal Muscle in Amyotrophic Lateral Sclerosis

The Role of Skeletal Muscle in Amyotrophic Lateral Sclerosis

Thermal stimulation at 39°C facilitates the fusion and elongation of C2C12 myoblasts

IRE1-XBP1 Pathway of the Unfolded Protein Response Is Required during Early Differentiation of C2C12 Myoblasts

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