Visceral myopathies are rare genetic disorders characterized by chronic intestinal pseudo-obstruction, severe abdominal pain, and recurrent vomiting, affecting an estimated 21–24 individuals per million worldwide - particularly children. These conditions arise from dysfunction of visceral smooth muscle cells (SMCs), yet the upstream regulatory mechanisms governing SMC phenotype and contractility remain poorly defined. Ubiquitin (Ub)-dependent signaling regulates protein turnover and activity and thereby influences diverse cellular processes, but its role in visceral myopathy has rarely been explored. Here, we identify a critical function for the E3 Ub ligase ARIH1 in maintaining visceral SMC phenotype and gastrointestinal (GI) motility. ARIH1 is broadly expressed across tissues. In silico analyses of publicly available bulk and single-cell RNA-seq datasets from patients and mouse models of visceral myopathy revealed dysregulated ARIH1 expression in degenerated visceral SMCs. Pan-SMC deletion of Arih1 (Myh11-Cre) resulted in GI pseudo-obstruction, marked distension of the GI tract, and severe dysmotility in the cecum and colon, ultimately causing premature lethality by ~4 weeks of age. Histological evaluation, GI transit assays, and muscle myography demonstrated pronounced dilation, extensive fibrosis, elastin disorganization, significantly delayed transit, and impaired contractility in mutant GI segments. Bulk RNA-seq of the muscularis revealed a robust shift toward an SMC synthetic phenotype, characterized by upregulation of extracellular matrix genes and downregulation of canonical SMC contractile genes. Consistent with these findings, ARIH1 silencing in human colonic SMCs reduced expression of contractile markers and diminished contractile function. Together, these data identify ARIH1 as an essential regulator of GI SMC contractile integrity and suggest that loss of ARIH1 function may contribute to human visceral myopathy. To our knowledge, this work represents one of the first mechanistic links between a ubiquitin E3 ligase and visceral SMC dysfunction, establishing Ub signaling as a promising area for therapeutic exploration in visceral myopathies. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Su et al. (Fri,) studied this question.