Cell Death and Disease (Apr 2022)

Long noncoding RNA ZFP36L2-AS functions as a metabolic modulator to regulate muscle development

  • Bolin Cai,
  • Manting Ma,
  • Jing Zhang,
  • Shaofen Kong,
  • Zhen Zhou,
  • Zhenhui Li,
  • Bahareldin Ali Abdalla,
  • Haiping Xu,
  • Xiquan Zhang,
  • Raman Akinyanju Lawal,
  • Qinghua Nie

DOI
https://doi.org/10.1038/s41419-022-04772-2
Journal volume & issue
Vol. 13, no. 4
pp. 1 – 12

Abstract

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Abstract Skeletal muscle is the largest metabolic organ in the body, and its metabolic flexibility is essential for maintaining systemic energy homeostasis. Metabolic inflexibility in muscles is a dominant cause of various metabolic disorders, impeding muscle development. In our previous study, we found lncRNA ZFP36L2-AS (for “ZFP36L2-antisense transcript”) is specifically enriched in skeletal muscle. Here, we report that ZFP36L2-AS is upregulated during myogenic differentiation, and highly expressed in breast and leg muscle. In vitro, ZFP36L2-AS inhibits myoblast proliferation but promotes myoblast differentiation. In vivo, ZFP36L2-AS facilitates intramuscular fat deposition, as well as activates fast-twitch muscle phenotype and induces muscle atrophy. Mechanistically, ZFP36L2-AS interacts with acetyl-CoA carboxylase alpha (ACACA) and pyruvate carboxylase (PC) to induce ACACA dephosphorylation and damaged PC protein stability, thus modulating muscle metabolism. Meanwhile, ZFP36L2-AS can activate ACACA to reduce acetyl-CoA content, which enhances the inhibition of PC activity. Our findings present a novel model about the regulation of lncRNA on muscle metabolism.