Journal of Biological Chemistry
Volume 296, January–June 2021, 100376
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Research Article
Lnc-ORA interacts with microRNA-532-3p and IGF2BP2 to inhibit skeletal muscle myogenesis

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Skeletal muscle is one of the most important organs of the animal body. Long noncoding RNAs play a crucial role in the regulation of skeletal muscle development via several mechanisms. We recently identified obesity-related lncRNA (lnc-ORA) in a search for long noncoding RNAs that influence adipogenesis, finding it impacted adipocyte differentiation by regulating the PI3K/protein kinase B/mammalian target of rapamycin pathway. However, whether lnc-ORA has additional roles, specifically in skeletal muscle myogenesis, is not known. Here, we found that lnc-ORA was significantly differentially expressed with age in mouse skeletal muscle tissue and predominantly located in the cytoplasm. Overexpression of lnc-ORA promoted C2C12 myoblast proliferation and inhibited myoblast differentiation. In contrast, lnc-ORA knockdown repressed myoblast proliferation and facilitated myoblast differentiation. Interestingly, silencing of lnc-ORA rescued dexamethasone-induced muscle atrophy in vitro. Furthermore, adeno-associated virus 9–mediated overexpression of lnc-ORA decreased muscle mass and the cross-sectional area of muscle fiber by upregulating the levels of muscle atrophy–related genes and downregulating the levels of myogenic differentiation–related genes in vivo. Mechanistically, lnc-ORA inhibited skeletal muscle myogenesis by acting as a sponge of miR-532-3p, which targets the phosphatase and tensin homolog gene; the resultant changes in phosphatase and tensin homolog suppressed the PI3K/protein kinase B signaling pathway. In addition, lnc-ORA interacted with insulin-like growth factor 2 mRNA-binding protein 2 and reduced the stability of myogenesis genes, such as myogenic differentiation 1 and myosin heavy chain. Collectively, these findings indicate that lnc-ORA could be a novel underlying regulator of skeletal muscle development.

Keywords

skeletal muscle
myogenesis
lnc-ORA
miR-532-3p
insulin-like growth factor 2 mRNA-binding protein 2
PTEN/PI3K/AKT signaling pathway

Abbreviations

AAV
adeno-associated virus
Dex
dexamethasone
EdU
5-ethynyl-20-deoxyuridine
GAS
gastrocnemius
GO
Gene Ontology
IGF2BP2
insulin-like growth factor 2 mRNA-binding protein 2
KEGG
Kyoto Encyclopedia of Genes and Genomes
lnc-ORA
obesity-related lncRNA
lncRNAs
long noncoding RNAs
MAFbx
muscle atrophy F-box
MRFs
myogenic regulatory factors
MuRF1
muscle RING finger 1
MyHC
myosin heavy chain
MyoG
myogenin
MyoD
myogenic differentiation 1
PTEN
phosphatase and tensin homolog
RIP
RNA immunoprecipitation
silnc-ORA
siRNA-lnc-ORA

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These authors contributed equally to this work.