Visceral myopathy: clinical syndromes, genetics, pathophysiology, and fall of the cytoskeleton

Abstract

Visceral smooth muscle is a crucial component of the walls of hollow organs like the gut, bladder, and uterus. This specialized smooth muscle has unique properties that distinguish it from other muscle types and that facilitate robust dilation and contraction. Visceral myopathies are diseases where severe visceral smooth muscle dysfunction prevents efficient movement of air and nutrients though the bowel, impairs bladder emptying, and affects normal uterine contraction and relaxation, particularly during pregnancy. Disease severity exists along a spectrum. The most debilitating defects cause highly dysfunctional bowel, reduced intrauterine colon growth (microcolon), and bladder emptying defects requiring catheterization, a condition called Megacystis Microcolon Intestinal Hypoperistalsis Syndrome (MMIHS). People with MMIHS often die early in childhood. When the bowel is the main organ affected and microcolon is absent, the condition is known as myopathic chronic intestinal pseudo-obstruction (CIPO). Visceral myopathies like MMIHS and myopathic CIPO are most commonly caused by mutations in contractile apparatus cytoskeletal proteins. Here, we review visceral myopathy-causing mutations and normal functions of these disease-associated proteins. We propose molecular, cellular, and tissue-level models that may explain clinical and histopathological features of visceral myopathy and hope these observations prompt new mechanistic studies.

High-Resolution Ultrasound and Speckle Tracking: a non-invasive approach to assess in vivo gastrointestinal motility during development

“…Recently, it was reported that the ACTG2 gene, which encodes gSMA, is mutated in 30% of children with CIPO who have a worse outcomes and severe GI dysmotility often associated with the presence of megacystis (Hashmi et al, 2021;Matera et al, 2016). In pediatric patients with CIPO, prenatal signs are detected only in about 20% of cases, mainly the presence of megacystis, although 50-70% of infants show clinical signs in the first month after birth (Di Nardo et al, 2017).…”

“…The pediatric Chronic Intestinal Pseudo-Obstruction (CIPO) syndrome is the most severe functional gastrointestinal disorder (high morbidity and mortality rates), but lacks standardized diagnostic and therapeutic approaches (Thapar et al, 2018). Recently, it was reported that the ACTG2 gene, which encodes ΨSMA, is mutated in 30% of children with CIPO who have a worse outcomes and severe GI dysmotility often associated with the presence of megacystis (Hashmi et al, 2021; Matera et al, 2016). In pediatric patients with CIPO, prenatal signs are detected only in about 20% of cases, mainly the presence of megacystis, although 50–70% of infants show clinical signs in the first month after birth (Di Nardo et al, 2017).…”

A transcriptome atlas of the mouse iris at single-cell resolution defines cell types and the genomic response to pupil dilation

“…The most severe inherited disorders of smooth muscle cell function, referred to as multisystemic smooth muscle dysfunction syndrome (MSMDS) or megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS), manifest in infancy with life-threatening defects in GI motility and are associated with mutations in the genes coding for components of the contractile machinery, including myosin light chain kinase ( MYLK ), SMA ( ACTA2 ), and myosin heavy chain-11 ( MYH11 ) ( Moreno et al, 2016 ; Gamboa and Sood, 2019 ; Hashmi et al, 2021 ). Defects in pupil constriction have been reported in patients with MSMDS/MMIHS, consistent with contractile defects in iris smooth muscle ( Moller et al, 2012 ; Roulez et al, 2014 ).…”

Wear and Tear of the Intestinal Visceral Musculature by Intrinsic and Extrinsic Factors

“…Given that DSS administration is used to model IBD in zebrafish and other animal models (Chuang et al, 2019; Kiesler et al, 2015; Oehlers et al, 2013; Oehlers et al, 2017), our findings raise the possibility that disruption of the visceral muscle structure could be an aspect of IBD. It has been shown that gastrointestinal motility disorders are frequently associated with IBD (Bassotti et al, 2014; Hashmi et al, 2021). Therefore, it would be interesting to investigate whether the visceral musculature is affected in IBD animal models and patients.…”