Folic acid is necessary for proliferation and differentiation of C2C12 myoblasts

Hwang, Soo Hyun; Kang, Yong‐Kook; Sung, Bokyung; Jang, Jung Yoon; Hwang, Na Lam; Oh, Hyo-Jung; Ahn, Yu Ra; Kim, Hong Jae; Shin, Jin‐Hong; Yoo, Mi‐Ae; Kim, Cheol Min; Chung, Hae Young; Kim, Nam Deuk

doi:10.1002/jcp.25989

Cited by 48 publications

(36 citation statements)

References 46 publications

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“…This apparent inconsistency might be explained in part by our previous observation that the inhibition of such differentiation by PDZRN3 depletion is mediated by the up-regulation of Id2 16 . DNA damage before the induction of myoblasts to myotubes differentiation has also been shown to inhibit the differentiation process 32,33 .…”

Section: Discussionmentioning

confidence: 99%

PDZRN3 protects against apoptosis in myoblasts by maintaining cyclin A2 expression

Honda

Inui

2020

Sci Rep

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PDZRN3 is a PDZ domain-containing RING-finger family protein that functions in various developmental processes. We previously showed that expression of PDZRN3 is induced together with that of MyoD during the early phase of skeletal muscle regeneration in vivo. We here show that PDZRN3 suppresses apoptosis and promotes proliferation in myoblasts in a manner dependent on cyclin A2. Depletion of PDZRN3 in mouse C2C12 myoblasts by RNA interference reduced the proportion of Ki-67-positive cells and the level of Akt phosphorylation, implicating PDZRN3 in regulation of both cell proliferation and apoptosis. Exposure of C2C12 cells as well as of C3H10T1/2 mesenchymal stem cells and NIH-3T3 fibroblasts to various inducers of apoptosis including serum deprivation resulted in a greater increase in the amount of cleaved caspase-3 in PDZRN3-depleted cells than in control cells. The abundance of cyclin A2 was reduced in PDZRN3-depleted C2C12 myoblasts, as was that of Mre11, which contributes to the repair of DNA damage. Overexpression of cyclin A2 restored the expression of Mre11 and Ki-67 as well as attenuated caspase-3 cleavage in PDZRN3-depleted cells deprived of serum. These results indicate that PDZRN3 suppresses apoptosis and promotes proliferation in myoblasts and other cell types by maintaining cyclin A2 expression.PDZ domain-containing RING-finger protein 3 (PDZRN3 or LNX3) was originally identified in silico as a homolog of LNX1 (PDZRN2), whose function as E3 ubiquitin ligase for NUMB is thought to contribute to cell fate determination at the level of inhibition of Notch signaling 1 . Although both LNX1 and PDZRN3 contain an NH 2 -terminal RING domain and a COOH-terminal consensus binding motif for the PDZ domain, LNX1 possesses four PDZ domains in its central region whereas PDZRN3 has only two. We first cloned PDZRN3 cDNA from human heart, and we showed that the protein is also expressed in various other human tissues including skeletal muscle, brain, and liver 2 . Subsequent studies implicated PDZRN3 in developmental processes such as the differentiation of myoblasts 2 , osteoblasts 3 , and adipocytes 4 , neurogenesis 5 , vascular morphogenesis 6 , maintenance of endothelial intercellular junctions 7 , and control both of paracellular Mg 2+ flux in renal tubular epithelial cells 8 and of the spatial arrangement of neurons 9 . Mutations of the PDZRN3 gene have also been identified in several tumor types 10-15 .Regeneration of skeletal muscle is initiated by the activation of satellite cells (myogenic stem cells) in response to injury. These cells give rise to myoblasts that express the transcription factor MyoD, proliferate (early phase of differentiation), and subsequently differentiate into myocytes that express the transcription factor myogenin and fuse to form myotubes (late phase of differentiation). We previously showed that depletion of PDZRN3 inhibited the late phase of differentiation of myocytes into myotubes 2,16 , and that the expression of PDZRN3 is induced together with that of MyoD during regeneration...

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Section: Discussionmentioning

confidence: 99%

PDZRN3 protects against apoptosis in myoblasts by maintaining cyclin A2 expression

Honda

Inui

2020

Sci Rep

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“…Replenishing the intracellular folate pool by the intake of exogenous folates, such as folic acid, is especially important for rapidly dividing cells, including cancer cells. Ample preclinical evidence links cellular replication to folate availability [16][17][18][19][20][21][22][23]. Such a link raised the concern that excessive consumption of dietary folate or folic acid may promote the progression of neoplastic lesions and increase the risk of malignancies and cancer-related death [11,[24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Effects of folic acid withdrawal on transcriptomic profiles in murine triple-negative breast cancer cell lines

et al. 2020

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“…Few studies have explicitly reported that MondoA is involved in myoblast differentiation. The myogenic genes MyHC, MyoG, and IGF2 are necessary for driving early and late skeletal muscle differentiation [ 30 31 ]. We demonstrated that the transcription factor MondoA promotes myoblast differentiation by increasing the expression of these myogenic genes.…”

Section: Discussionmentioning

confidence: 99%

MondoA Is Required for Normal Myogenesis and Regulation of the Skeletal Muscle Glycogen Content in Mice

Hui

Zhang

et al. 2021

Diabetes Metab J

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Background: Skeletal muscle is the largest tissue in the human body, and it plays a major role in exerting force and maintaining metabolism homeostasis. The role of muscle transcription factors in the regulation of metabolism is not fully understood. Mon-doA is a glucose-sensing transcription factor that is highly expressed in skeletal muscle. Previous studies suggest that MondoA can influence systemic metabolism homeostasis. However, the function of MondoA in the skeletal muscle remains unclear. Methods: We generated muscle-specific MondoA knockout (MAKO) mice and analyzed the skeletal muscle morphology and glycogen content. Along with skeletal muscle from MAKO mice, C2C12 myocytes transfected with small interfering RNA against MondoA were also used to investigate the role and potential mechanism of MondoA in the development and glycogen metabolism of skeletal muscle. Results: MAKO caused muscle fiber atrophy, reduced the proportion of type II fibers compared to type I fibers, and increased the muscle glycogen level. MondoA knockdown inhibited myoblast proliferation, migration, and differentiation by inhibiting the phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase (PI3K)/Akt pathway. Further mechanistic experiments revealed that the increased muscle glycogen in MAKO mice was caused by thioredoxin-interacting protein (TXNIP) downregulation, which led to upregulation of glucose transporter 4 (GLUT4), potentially increasing glucose uptake. Conclusion: MondoA appears to mediate mouse myofiber development, and MondoA decreases the muscle glycogen level. The findings indicate the potential function of MondoA in skeletal muscle, linking the glucose-related transcription factor to myogenesis and skeletal myofiber glycogen metabolism.

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Folic acid is necessary for proliferation and differentiation of C2C12 myoblasts

Cited by 48 publications

References 46 publications

PDZRN3 protects against apoptosis in myoblasts by maintaining cyclin A2 expression

PDZRN3 protects against apoptosis in myoblasts by maintaining cyclin A2 expression

Effects of folic acid withdrawal on transcriptomic profiles in murine triple-negative breast cancer cell lines

MondoA Is Required for Normal Myogenesis and Regulation of the Skeletal Muscle Glycogen Content in Mice

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