CircSMOX in muscle and neuronal physiology and disease

Abstract Circular RNAs (circRNAs) are single stranded RNA molecules with a covalently closed loop structure that confers remarkable stability. They are increasingly recognized as important regulators of gene expression, showing tissue- and stage-specific expression patterns. CircRNAs influence gene expression through several routes: many sequester microRNAs, others bind specific RNA-binding proteins, and some affect transcription or post-transcriptional control. A subset can even be translated into short peptides. They are particularly abundant in the nervous system and in skeletal muscle, where they contribute to processes such as neural development, synaptic function, neuronal plasticity, muscle formation, and tissue homeostasis. Disruptions in circRNA expression patterns have been linked to neurodegenerative conditions, muscle-wasting disorders, and other disease states. Among the known circRNAs, circSMOX-formed from exons 2 and 3 of the murine SMOX gene-has been found dynamically expressed during brain and muscle development and increased in models of ischemia, spinal cord damage, and muscle atrophy. During C2C12 myogenic differentiation, circSMOX expression parallels that of the linear SMOX transcript. In contrast, in dexamethasone-induced atrophy and in ALS mouse models (SOD1 G93A and hFUS +/+ ), which exhibit progressive muscle atrophy, circSMOX is significantly upregulated. Mainly localized in the cytoplasm and less abundant than the linear isoform, circSMOX acts as a miR-340-5p sponge, influencing neuroinflammatory pathways. Despite these insights, the precise molecular mechanisms of circSMOX remain to be fully clarified, and the identification of a human ortholog will be important to broaden its therapeutic potential.