Long Noncoding RNA SMUL Suppresses SMURF2 Production-mediated Muscle Atrophy via Nonsense-mediated mRNA Decay

Abstract As the world population grows, muscle atrophy leading to muscle wasting could become a bigger risk. Long noncoding RNAs (lncRNAs) is known to play important roles in muscle growth and muscle atrophy. Meanwhile, it has recently come to light that many putative small ORFs (sORFs) are hidden in lncRNAs, however, their translational capabilities and functions remain unclear. In this study, we uncovered 104 myogenic associated-lncRNAs translated, in at least, a small peptide, by integrated transcriptome and proteomic analyses. Furthermore, an upstream ORFs (uORFs) regulatory network was constructed, and a novel muscle atrophy associated-lncRNA named SMUL (for “SMURF2 upstream lncRNA”) was identified. SMUL was highly expressed in skeletal muscle, and its expression level was downregulated during myoblasts differentiation. SMUL promoted myoblast proliferation and suppressed differentiation in vitro. In vivo, SMUL induced skeletal muscle atrophy and promoted a switch from slow twitch to fast-twitch fibers. In the meantime, translation of the SMUL sORF disrupted the stability of SMURF2 mRNA. Mechanistically, SMUL restrained SMURF2 production via nonsense-mediated mRNA decay (NMD), participating in the regulation of TGF-β/SMAD pathway and further regulating in myogenesis and muscle atrophy. Taken together, these results suggest that SMUL could be a novel therapeutic target for muscle atrophy.