Structural and functional changes in the gastrointestinal tract of the ACTA2 R179H mouse model of multisystemic smooth muscle dysfunction syndrome

Multisystemic Smooth Muscle Dysfunction Syndrome (MSMDS) is a rare disorder caused by ACTA2 mutations, including the R179H variant, which disrupts actin polymerization and smooth muscle contractility. While cardiovascular complications dominate its clinical presentation, gastrointestinal (GI) dysfunction significantly impacts quality of life. To investigate the structural, functional, and cellular basis of gut dysmotility in MSMDS, we studied the ACTA2 R179H mouse model and reviewed clinical data from 24 MSMDS patients. Patients exhibited severe gut dysmotility, with 75% requiring medication for chronic constipation. ACTA2 mutant mice displayed cecal and colonic dilatation, reduced intestinal length, and disrupted colonic migrating motor complexes (CMMCs). Delayed whole-gut transit and impaired contractile responses to electrical and pharmacological stimulation were observed. Transcriptomic analysis revealed significant actin cytoskeleton-related gene changes in smooth muscle cells, and immune profiling identified increased lymphocytic infiltration. Despite functional abnormalities, enteric neuronal populations remained unchanged. These findings establish ACTA2 mice as a robust model for studying GI pathology in MSMDS, elucidating the role of smooth muscle dysfunction in gut dysmotility. This model provides a foundation for developing targeted therapies aimed at restoring intestinal motility by directly addressing actin cytoskeletal disruptions in smooth muscle cells.