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PPARGC1A Is a Moderator of Skeletal Muscle Development Regulated by miR-193b-3p.

ABSTRACT: Meat production performance is one of the most important factors in determining the economic value of poultry. Myofiber is the basic unit of skeletal muscle, and its physical and chemical properties determine the meat quality of livestock and poultry to a certain extent. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) as a transcriptional coactivator has been found to be widely involved in a series of biological processes. However, PPARGC1A is still poorly understood in chickens. In this manuscript, we reported that PPARGC1A was highly expressed in slow-twitch myofibers. PPARGC1A facilitated mitochondrial biogenesis and regulated skeletal muscle metabolism by mediating the flux of glycolysis and the TCA cycle. Gain- and loss-of-function analyses revealed that PPARGC1A promoted intramuscular fatty acid oxidation, drove the transformation of fast-twitch to slow-twitch myofibers, and increased chicken skeletal muscle mass. Mechanistically, the expression level of PPARGC1A is regulated by miR-193b-3p. Our findings help to understand the genetic regulation of skeletal muscle development and provide a molecular basis for further research on the antagonism of skeletal muscle development and fat deposition in chickens.

SUBMITTER: Ma M

PROVIDER: S-EPMC9455960 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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PPARGC1A Is a Moderator of Skeletal Muscle Development Regulated by miR-193b-3p.

Ma Manting M Cai Bolin B Kong Shaofen S Zhou Zhen Z Zhang Jing J Zhang Xiquan X Nie Qinghua Q

International journal of molecular sciences 20220824 17

Meat production performance is one of the most important factors in determining the economic value of poultry. Myofiber is the basic unit of skeletal muscle, and its physical and chemical properties determine the meat quality of livestock and poultry to a certain extent. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) as a transcriptional coactivator has been found to be widely involved in a series of biological processes. However, PPARGC1A is still ...[more]

PMID: 36076970

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Project description:BackgroundTumor metastasis is responsible for approximately 90% of mortality in lung cancer. Understanding the molecular mechanisms of lung cancer metastasis is crucial for developing new treatment strategies. Cellular prion protein (PrPc), encoded by PRNP gene, was previously found to enhance lung cancer invasiveness. However, research on the post-transcriptional regulation of PRNP remains limited.MethodsDual-luciferase reporter assays identified miRNAs targeting the PRNP 3'-UTR, and RNA immunoprecipitation (RIP) confirmed the interaction between miR-193b-3p and PRNP mRNA. Promoter deletions and chromatin immunoprecipitation (ChIP) assays established c-Jun as a transcriptional repressor of miR-193b-3p. Functional validation of the c-Jun-miR-193b-3p-PrPc axis was conducted using transwell assays, LNA-in situ hybridization, RT-PCR, Western blot, and immunohistochemistry. Subcutaneous mouse xenograft models assessed the anti-tumor effects of miR-193b-3p in vivo.ResultsWe demonstrated that miR-193b-3p downregulates PrPc expression by directly targeting the 3'-UTR of PRNP. Overexpression of miR-193b-3p significantly suppressed PRNP expression at both mRNA and protein levels, and reduced lung cancer cell migration, invasion and proliferation, which was reversed by PrPc overexpression. Conversely, miR-193b-3p silencing enhanced PRNP expression as well as those oncogenic properties, which were mitigated by PRNP knockdown. Spearman correlation analysis revealed a significant negative association between miR-193b-3p and PrPc expression in lung cancer tissues (p = 0.017), and Kaplan-Meier survival analysis demonstrated that high PrPc (p = 0.039) or low miR-193b-3p (p = 0.027) expression correlated with poorer overall survival. Intra-tumoral injection of the miR-193b-3p mimic in mouse xenograft models significantly reduced tumor volume. In addition, c-Jun was identified as a transcriptional repressor of miR-193b-3p. Functional studies revealed that c-Jun knockdown inhibited lung cancer cell migration, invasion, and proliferation, effects that were reversed by either PrPc overexpression or miR-193b-3p inhibitor treatment. A significant association between PrPc and c-Jun expression in lung cancer tissues (p = 0.004) was observed. High expression of PrPc and/or c-Jun was found to be associated with poor overall survival of patients (p < 0.05).ConclusionsThis study is the first to uncover a novel regulatory pathway where c-Jun acts as a transcriptional repressor of miR-193b-3p, leading to PRNP upregulation, which promotes lung cancer migration and invasion. This previously unrecognized c-Jun-miR-193b-3p-PrPc axis also provides valuable insights for the potential development of new therapeutic strategies against lung cancer metastasis through RNA-targeting technology.

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PPARGC1A Is a Moderator of Skeletal Muscle Development Regulated by miR-193b-3p.

Publications

<i>PPARGC1A</i> Is a Moderator of Skeletal Muscle Development Regulated by <i>miR-193b-3p</i>.

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