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

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 IncRNA 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 IncRNA on muscle metabolism.

Automated summary

This study discovers a long non-coding RNA called ZFP36L2-AS that plays a crucial role in regulating muscle metabolism. It promotes myoblast differentiation while inhibiting myoblast proliferation, and also contributes to intramuscular fat deposition and muscle atrophy.