Table 2.

New hypotheses to understand visceral myopathy

ACTG2 variants that impair actin polymerization may increase cytoplasmic sequestration of MRTFs by G-actin. Reduced nuclear MRTFs can decrease SMC contractile gene expression and increase expression of ECM and promitogenic genes.

Stiffening of bowel and bladder due to fibrosis and pathological stretch may promote nuclear localization of YAP, which inhibits myocardin and downregulates expression of SMC contractile genes.

NF-κB activation by pro-inflammatory cytokines may inhibit SMC contractile gene expression because NF-κB inhibits myocardin.

Cytoskeletal gene mutations that reduce F-actin interactions with myosin or interactions between actin and focal adhesions may reduce 1) force generation, 2) force transmission to the ECM, and 3) the ability of muscle to resist passive stretch. Cytoskeletal gene mutations may impair force transmission to the nucleus via the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, further reducing SMC contractile gene expression in response to extracellular forces.

Drastically increased protein production in synthetic phenotype SMCs may trigger an unfolded protein response (UPR), an ER stress response, reinforcing a vicious cycle that further reduces SMC contractile gene expression.

Rapamycin and Lovastatin may increase expression of SMC contractile genes, enhancing SMC force generation. Antifibrotics may make the ECM more pliable and reduce the stiffness of the SMC microenvironment. Gene targeting approaches can be considered to silence mutations or correct them.

ACTG2, actin gamma 2; ECM, extracellular matrix; ER, endoplasmic reticulum; G-actin, globular actin; MRTFs, myocardin-related transcription factors; SMC, smooth muscle cell; YAP, Yes-associated protein.