Tiny Regulators of Massive Tissue: MicroRNAs in Skeletal Muscle Development, Myopathies, and Cancer Cachexia

Singh, Gurdeep; Cowan, Douglas B.; Wang, Dazhi

doi:10.3389/fonc.2020.598964

Cited by 29 publications

(25 citation statements)

References 147 publications

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“…MicroRNAs (miRNAs), a new class of cell lineage regulators, are also involved throughout the process of embryonic development and cellular differentiation (Ivey and Srivastava, 2010;Vidigal and Ventura, 2015;Singh et al, 2020). Most importantly, many miRNAs, especially muscle-specific clusters, such as the miR-1a and miR-133 families, are required for muscle development and must be subject to strict dynamic regulation during rapid developmental transitions or changes in the cellular environment (Rao et al, 2006;Liu et al, 2007;Braun and Gautel, 2011).…”

Section: Introductionmentioning

confidence: 99%

PERK Signaling Controls Myoblast Differentiation by Regulating MicroRNA Networks

Tan

Zhang

et al. 2021

Front. Cell Dev. Biol.

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The unfolded protein response (UPR) plays important roles in various cells that have a high demand for protein folding, which are involved in the process of cell differentiation and development. Here, we separately knocked down the three sensors of the UPR in myoblasts and found that PERK knockdown led to a marked transformation in myoblasts from a fusiform to a rounded morphology, which suggests that PERK is required for early myoblast differentiation. Interestingly, knocking down PERK induced reprogramming of C2C12 myoblasts into stem-like cells by altering the miRNA networks associated with differentiation and stemness maintenance, and the PERK-ATF4 signaling pathway transactivated muscle differentiation-associated miRNAs in the early stage of myoblast differentiation. Furthermore, we identified Ppp1cc as a direct target gene of miR-128 regulated by the PERK signaling pathway and showed that its repression is critical for a feedback loop that regulates the activity of UPR-associated signaling pathways, leading to cell migration, cell fusion, endoplasmic reticulum expansion, and myotube formation during myoblast differentiation. Subsequently, we found that the RNA-binding protein ARPP21, encoded by the host gene of miR-128-2, antagonized miR-128 activity by competing with it to bind to the 3′ untranslated region (UTR) of Ppp1cc to maintain the balance of the differentiation state. Together, these results reveal the crucial role of PERK signaling in myoblast maintenance and differentiation and identify the mechanism underlying the role of UPR signaling as a major regulator of miRNA networks during early differentiation of myoblasts.

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Section: Introductionmentioning

confidence: 99%

PERK Signaling Controls Myoblast Differentiation by Regulating MicroRNA Networks

Tan

Zhang

et al. 2021

Front. Cell Dev. Biol.

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“…Skeletal muscle metabolism plays a crucial role in the pathogenesis of cachexia in cancer patients ( 44 ), where miRNAs are abundantly expressed in skeletal muscles and are involved in cancer cachexia. Numerous miRNAs are known to modulate skeletal muscle and adipose tissue turnover; therefore, the potential of miRNAs as predictor biomarkers and their clinical relevance in cachexia have been previously suggested ( 45 ). Indeed, their aberrant expression is associated with impaired myogenesis, consequently promoting the development of cachexia ( 13 , 46 ).…”

Section: Discussionmentioning

confidence: 99%

Impact of TNF-α Gene Polymorphisms on Pancreatic and Non-Small Cell Lung Cancer-Induced Cachexia in Adult Egyptian Patients: A Focus on Pathogenic Trajectories

et al. 2021

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BackgroundCachexia is a frequent syndrome in pancreatic and non-small cell lung (NSCL) cancer patients. The storm of cancer-induced inflammatory cytokines, in particular TNF-α, is a crucial pathogenic mechanism. Among the molecular alterations accused of cancer-induced cachexia, TNF-α 308 G/A (rs1800629) and −1031T/C (rs1799964) are single-nucleotide polymorphisms (SNPs) within the gene encoding this pro-inflammatory cytokine. Recent studies have demonstrated the crucial role of non-coding microRNAs (miRNAs) in pathogenesis of different diseases including cachexia. Moreover, the mechanistic cytokine signaling pathway of miR-155, as a TNF-α regulator, supports the involvement of SOCS1, TAB2, and Foxp3, which are direct targets of TNF-α gene.AimA case–control study (NCT04131478) was conducted primarily to determine the incidence of TNF-α 308 G/A (rs1800629) and −1031T/C (rs1799964) gene polymorphisms in adult Egyptian patients with local/advanced or metastatic pancreatic or NSCL cancer and investigate both as cachexia risk factors. The association of gene polymorphism with cachexia severity and the expression of miR-155 in cachectic patients were analyzed. A mechanistic investigation of the cytokine signaling pathway, involving SOCS1, TAB2, and Foxp3, was also performed.ResultsIn both pancreatic and NSCL cancer cohorts, the mutant TNF-α variant of 308 G/A was positively associated with cachexia; on the contrary, that of 1031T/C was negatively associated with cachexia in the NSCL cancer patients. MiR-155 was higher in cachexia and in alignment with its severity in the cachectic group as compared with the non-cachectic group in both the pancreatic and NSCL cancer patients. Though TAB2 did not change to any significant extent in cachectic patients, the levels of SOCS1 and Foxp3 were significantly lower in the cachectic group as compared with the non-cachectic group.ConclusionCarriers of the A allele 308 G/A gene and high miR-155 are at greater risk of cachexia in both the pancreatic and NSCL cancer patients; however, the mutant variant of 1031T/C gene is protective against cachexia in the NSCL cancer patients. Finally, high levels of miR-155 in the cachectic group lead to negative feedback inhibition of both SOCS1 and Foxp3 in both the pancreatic and NSCL cancer patients.

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“…Both mRNA and protein levels were reduced during differentiation. It is well established that miRNAs play an important role during the myogenic differentiation process, and we and others have previously validated the upregulation of myomiRs whose expression increase manifold (27)(28)(29)(30). We searched for the candidate miRNAs with potential binding sites in the 3'-UTR of Cap1, using our own published set of myomiRs in C2C12 cells (GSE136956) (27).…”

Section: Discussionmentioning

confidence: 99%

“…Since Cap1 is downregulated both at the mRNA and the protein level, we looked for the mechanism that might regulate the expression of Cap1 during differentiation. It is well established that the differentiation process of skeletal muscle involves miRNA called myomiRs which are upregulated manifold during differentiation (27)(28)(29)(30). We thus revisited our own published dataset (GSE136956) (27) for differentiation-induced miRNA which might have potential binding sites in the 3'-UTR of Cap1.…”

Section: Regulation Of Cap1 Expression By Known Myomirs During Differentiationmentioning

confidence: 99%

miRNA mediated downregulation of non-muscle Cyclase associated protein 1 is required for myogenic differentiation

Singh

Rai

Weber

et al. 2021

Preprint

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Myoblast fusion is crucial for the formation, growth and regeneration of healthy skeletal muscle, but the molecular mechanisms that govern fusion and myofiber formation remain poorly understood. Here we report that Cyclase-associated protein 1 (Cap1), a regulator of actin dynamics, plays a critical role in cytoskeletal remodeling during myoblast fusion and formation of myotubes. Cap1 mRNA and protein are expressed in murine C2C12 and human LHCN-M2 myoblasts, but its abundance decreases during myogenic differentiation. Perturbing the temporally controlled expression of Cap1 by overexpression or Crispr-Cas9 mediated knockout impaired actin rearrangement, myoblast alignment, expression of profusion molecules, differentiation into multinucleated myotubes and myosin heavy chain expression. Endogenous Cap1 expression is posttranscriptionally downregulated during differentiation by canonical myomiRs miR-1, miR-133 and miR-206, which have conserved binding sites in the 3’ UTR of the Cap1 mRNA. Deletion of the endogenous 3’ UTR in C2C12 cells phenocopies overexpression of Cap1 by inhibiting myotube formation. Our findings implicate Cap1 and its myomiR-mediated downregulation in the myoblast fusion process and the generation of skeletal muscle.

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Tiny Regulators of Massive Tissue: MicroRNAs in Skeletal Muscle Development, Myopathies, and Cancer Cachexia

Cited by 29 publications

References 147 publications

PERK Signaling Controls Myoblast Differentiation by Regulating MicroRNA Networks

PERK Signaling Controls Myoblast Differentiation by Regulating MicroRNA Networks

Impact of TNF-α Gene Polymorphisms on Pancreatic and Non-Small Cell Lung Cancer-Induced Cachexia in Adult Egyptian Patients: A Focus on Pathogenic Trajectories

miRNA mediated downregulation of non-muscle Cyclase associated protein 1 is required for myogenic differentiation

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