Structural and functional gastrointestinal abnormalities in ACTA2 R179H mice modeling multisystemic smooth muscle dysfunction syndrome
Ahmed A. Rahman, Rhian Stavely, Leah C. Ott, Christopher Y. Han, Kensuke Ohishi, Ryo Hotta, Alan J. Burns, Sabyasachi Das, Emily Da Cruz, Diana Tambala, Mark E. Lindsay, Patricia L. Musolino, Allan M. Goldstein
Ahmed A. Rahman, Rhian Stavely, Leah C. Ott, Christopher Y. Han, Kensuke Ohishi, Ryo Hotta, Alan J. Burns, Sabyasachi Das, Emily Da Cruz, Diana Tambala, Mark E. Lindsay, Patricia L. Musolino, Allan M. Goldstein
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Research Article Gastroenterology Neuroscience

Structural and functional gastrointestinal abnormalities in ACTA2 R179H mice modeling multisystemic smooth muscle dysfunction syndrome

Abstract

Multisystemic smooth muscle dysfunction syndrome (MSMDS) is a rare disorder caused by ACTA2 mutations, including the R179H variant, which alters actin filament stability and dynamics and smooth muscle contractility. Cardiovascular complications dominate its clinical presentation, but gastrointestinal (GI) dysfunction significantly affects quality of life. To investigate the structural, functional, and cellular basis of gut dysmotility in MSMDS, we reviewed clinical data from 24 patients with MSMDS and studied the ACTA2 R179H mouse model. 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. 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, there were no obvious changes in the enteric nervous system. 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.

Authors

Ahmed A. Rahman, Rhian Stavely, Leah C. Ott, Christopher Y. Han, Kensuke Ohishi, Ryo Hotta, Alan J. Burns, Sabyasachi Das, Emily Da Cruz, Diana Tambala, Mark E. Lindsay, Patricia L. Musolino, Allan M. Goldstein

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Figure 3

Reduced smooth muscle contraction in ACTA2 mutant mice in response to EFS, ACh, and KCl (distal colon).

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Reduced smooth muscle contraction in ACTA2 mutant mice in response to EF...
(A–C) Representative traces of smooth muscle contraction in response to EFS (A), ACh (B), and KCl (C) in distal colon rings from control and ACTA2 mice. Bar graphs depict the maximum contractile force (g) recorded within 5 minutes after stimulus addition, compared with the maximum value during the 60-second baseline period prior to stimulation. This difference was used to calculate the absolute change in response (Δg). (A) Application of EFS caused significant muscle contraction in the distal colon of control mice but no response in ACTA2 mice. Maximum effects are shown as the absolute change from basal values. (B) Both low and high doses of ACh failed to induce contraction in ACTA2 mice (left panel, representative trace). (C) Muscle contraction in response to KCl was also attenuated in ACTA2 mice. (D) TTX increased the frequency and amplitude of tonic contractions in control mice but had no effect on tissues from ACTA2 mice. Data are presented as mean ± SEM. Statistical comparisons were made using unpaired 2-tailed t tests, as detailed in Methods. **P < 0.01, ***P < 0.001.