Lnc-ORA interacts with microRNA-532-3p and IGF2BP2 to inhibit skeletal muscle myogenesis

Rui Cai; Que Zhang; Yingqian Wang; Wenlong Yong; Rui Zhao; Weijun Pang

doi:10.1016/j.jbc.2021.100376

Lnc-ORA interacts with microRNA-532-3p and IGF2BP2 to inhibit skeletal muscle myogenesis

J Biol Chem. 2021 Jan-Jun:296:100376. doi: 10.1016/j.jbc.2021.100376. Epub 2021 Feb 4.

Authors

Rui Cai¹, Que Zhang¹, Yingqian Wang¹, Wenlong Yong¹, Rui Zhao¹, Weijun Pang²

Affiliations

¹ Laboratory of Animal Fat Deposition and Muscle Development, Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China.
² Laboratory of Animal Fat Deposition and Muscle Development, Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China. Electronic address: pwj1226@nwsuaf.edu.cn.

Abstract

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

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipogenesis
Animals
Cell Differentiation / genetics
Cell Proliferation / genetics
Male
Mice
Mice, Inbred C57BL
MicroRNAs / genetics
MicroRNAs / metabolism
Muscle Development / genetics*
Muscle Fibers, Skeletal / metabolism
Muscle, Skeletal / metabolism
Muscular Atrophy / metabolism
Myoblasts / metabolism
Proto-Oncogene Proteins c-akt / metabolism
RNA, Long Noncoding / genetics
RNA-Binding Proteins / metabolism*
RNA-Binding Proteins / physiology
Signal Transduction

Substances

IGF2BP2 protein, mouse
MicroRNAs
RNA, Long Noncoding
RNA-Binding Proteins
Proto-Oncogene Proteins c-akt