Conservative analysis of Synaptopodin‐2 intron sense‐overlapping lncRNA reveals its novel function in promoting muscle atrophy

Background Dissection of the regulatory pathways that control skeletal muscle development and atrophy is important for the treatment of muscle wasting. Long noncoding RNA (lncRNA) play important roles in various stages of muscle development. We previously reported that Synaptopodin‐2 (SYNPO2) intron sense‐overlapping lncRNA (SYISL) regulates myogenesis through an interaction with enhancer of zeste homologue 2 (EZH2). However, it remains unclear whether SYISL homologues exist in humans and pigs, and whether the functions and mechanisms of these homologues are conserved among species. Methods Bioinformatics, cell fractionation, and quantitative real‐time polymerase chain reaction (qRT‐PCR) analyses were used for the identification and molecular characterization of SYISL homologues in humans and pigs. Effects on myogenesis and muscle atrophy were determined via loss‐of‐function or gain‐of‐function experiments using C2C12 myoblasts, myogenic progenitor cells, dexamethasone (DEX), and aging‐induced muscle atrophy models. RNA pulldown, RNA immunoprecipitation, dual luciferase reporting, and co‐transfection experiments were used to explore the mechanisms of SYISL interactions with proteins and miRNAs. Results We identified SYISL homologues in humans (designated hSYISL) and pigs (designated pSYISL). Functional experiments demonstrated that hSYISL and pSYISL regulate myogenesis through interactions with EZH2. Interestingly, we showed that SYISL functions to regulate muscle atrophy and sarcopenia through comparative analysis. SYISL is significantly up‐regulated after muscle atrophy (P