Visceral Myopathy: Clinical syndromes, genetics, pathophysiology, and Fall of the Cytoskeleton

2021 ◽  
Author(s):  
Sohaib Khalid Hashmi ◽  
Rachel Helen Ceron ◽  
Robert O Heuckeroth
Keyword(s):  
Smooth Muscle ◽  
Tissue Level ◽  
Cytoskeletal Proteins ◽  
Bladder Emptying ◽  
Visceral Myopathy ◽  
Crucial Component ◽  
Associated Proteins ◽  
Intestinal Pseudo Obstruction ◽  
Visceral Smooth Muscle ◽  
Contraction And Relaxation

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.

Mechanotransduction in gastrointestinal smooth muscle cells: Role of mechanosensitive ion channels

2021 ◽  
Author(s):  
Vikram Joshi ◽  
Peter R Strege ◽  
Gianrico Farrugia ◽  
Arthur Beyder
Keyword(s):  
Smooth Muscle ◽  
Ion Channels ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Tissue Level ◽  
Cytoskeletal Proteins ◽  
Cell Junction ◽  
Mechanical Stimuli ◽  
Junction Molecules

Mechanosensation, the ability to properly sense mechanical stimuli and transduce them into physiologic responses, is an essential determinant of gastrointestinal (GI) function. Abnormalities in this process result in highly prevalent GI functional and motility disorders. In the GI tract, several cell types sense mechanical forces and transduce them into electrical signals, which elicit specific cellular responses. Some mechanosensitive cells like sensory neurons act as specialized mechanosensitive cells that detect forces and transduce signals into tissue-level physiologic reactions. Non-specialized mechanosensitive cells like smooth muscle cells (SMCs) adjust their function in response to forces. Mechanosensitive cells utilize various mechanoreceptors and mechanotransducers. Mechanoreceptors detect and convert force into electrical and biochemical signals, and mechanotransducers amplify and direct mechanoreceptor responses. Mechanoreceptors and mechanotransducers include ion channels, specialized cytoskeletal proteins, cell junction molecules, and G-protein coupled receptors. SMCs are particularly important due to their role as final effectors for motor function. Myogenic reflex-the ability of smooth muscle to contract in response to stretch rapidly-is a critical smooth muscle function. Such rapid mechanotransduction responses rely on mechano-gated and -sensitive ion channels, which alter their ion pores' opening in response to force, allowing fast electrical and Ca2+ responses. Though GI SMCs express a variety of such ion channels, their identities remain unknown. Recent advancements in electrophysiological, genetic, in vivo imaging, and multi-omic technologies broaden our understanding of how SMC mechano-gated and -sensitive ion channels regulate GI functions. This review discusses GI SMC mechanosensitivity's current developments with a particular emphasis on mechano-gated and -sensitive ion channels.

scholarly journals Expression of intermediate filament-associated proteins paranemin and synemin in chicken development.

1983 ◽  
Vol 97 (6) ◽  
pp. 1860-1874 ◽  
Author(s):  
M G Price ◽  
E Lazarides
Keyword(s):  
Smooth Muscle ◽  
Intermediate Filament ◽  
Muscle Cells ◽  
Myocardial Cells ◽  
Adult Chicken ◽  
Intermediate Filament Proteins ◽  
Adult Muscle ◽  
Associated Proteins ◽  
Visceral Smooth Muscle ◽  
Chicken Development

The expression of two intermediate filament-associated proteins, paranemin (280,000 mol wt) and synemin (230,000 mol wt), was investigated with respect to the expression of two core intermediate filament proteins, desmin and vimentin, in various embryonic and adult chicken muscle and nonmuscle cells. All developing muscle cells, regardless of their type, simultaneously express desmin, vimentin, paranemin, and synemin. However, a difference is observed in the expression of paranemin in adult muscle. This protein is removed during differentiation of both fast and slow skeletal muscle, visceral smooth muscle, and the smooth muscle of muscular arteries, but remains in mature myocardial cells, cardiac conducting fibers, and the smooth muscle cells of elastic arteries. Some of these cells express vimentin, others desmin, and still others a mixture of the two. On the other hand, synemin is expressed in all the above types of adult muscle cells except myocardial cells. Adult myocardial cells also lack vimentin, and its presence is gradually reduced after hatching. Since in adult striated muscle all expressed intermediate filament proteins are found predominantly in association with the peripheries of myofibrillar Z discs, these results suggest that a change in the composition of skeletal and cardiac muscle Z discs occurs during chicken development and maturation. Erythrocytes that express synemin and vimentin do not express paranemin, while both embryonic and adult Schwann cells co-express paranemin and vimentin, but not synemin. Endothelial cells of muscular vessels express paranemin, while those of elastic vessels do not, and neither contains synemin. Paranemin and synemin are not expressed in neurons, epithelial, and most glial cells, suggesting that these two polypeptides are expressed only in conjunction with desmin or vimentin. These results suggest that the composition of intermediate filaments changes during chicken development, not only with respect to their core subunit proteins but also with respect to two associated polypeptides, particularly in muscle cells.

scholarly journals Chronic intestinal pseudo-obstruction in systemic lupus erythematosus

Gut ◽  
1998 ◽  
Vol 43 (1) ◽  
pp. 117-122 ◽  
Author(s):  
G Perlemuter ◽  
S Chaussade ◽  
B Wechsler ◽  
P Cacoub ◽  
M Dapoigny ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Smooth Muscle ◽  
Lupus Erythematosus ◽  
Bladder Capacity ◽  
High Dose ◽  
Systemic Lupus ◽  
Muscle Involvement ◽  
Antroduodenal Manometry ◽  
Intestinal Pseudo Obstruction ◽  
Visceral Smooth Muscle

Background/Aims—Chronic intestinal pseudo-obstruction (CIPO) reflects a dysfunction of the visceral smooth muscle or the enteric nervous system. Gastrointestinal manifestations are common in systemic lupus erythematosus (SLE) but CIPO has not been reported. Features of CIPO are reported in five patients with SLE.Methods—From 1988 to 1993, five patients with SLE or SLE-like syndrome were hospitalised for gastrointestinal manometric studies. CIPO was the onset feature in two cases. Antroduodenal manometry (three hours fasting, two hours fed) was performed in all patients, and oesophageal manometry in four.Results—Intestinal hypomotility associated with reduced bladder capacity and bilateral ureteral distension was found in four patients and aperistalsis of the oesophagus in three. Treatment, which consisted of high dose corticosteroids, parenteral nutrition, promotility agents, and antibiotics, led to remission of both CIPO and urinary abnormalities in all cases. Antroduodenal manometry performed in two patients after remission showed increased intestinal motility. One patient died, and postmortem examination showed intestinal vasculitis.Conclusions—CIPO in SLE is a life threatening situation that can be reversed by treatment. It may be: (a) a complication or onset feature of the disease; (b) secondary to smooth muscle involvement; (c) associated with ureteral and vesical involvement; (d) the result of intestinal vasculitis.

scholarly journals Molecular mechanisms involved in development of cerebral vasospasm

2002 ◽  
Vol 12 (3) ◽  
pp. 1-8 ◽  
Author(s):  
Eiichi Tani
Keyword(s):  
Smooth Muscle ◽  
Thin Filament ◽  
Molecular Mechanisms ◽  
Cytoskeletal Proteins ◽  
G Protein Coupled Receptors ◽  
Myosin Phosphatase ◽  
Associated Proteins ◽  
Intracellular Ca ◽  
G Protein Coupled ◽  
Kinase Pathway

Object Although the agents responsible for production of vasospasm have not yet been clearly identified, the author reviews the molecular mechanisms involved in development of vasospasm mainly based on the experimental data in a canine two-hemorrhage model. Methods The blood products after subarachnoid hemorrhage most likely stimulate many cell membrane receptors, such as G protein–coupled receptors and receptor tyrosine kinases, to activate the tyrosine kinase pathway of the vascular smooth muscle cells. The activation of the tyrosine kinase pathway is associated with continuous elevation of intracellular Ca++ levels and activation of μ-calpain; the former may result mainly not from Ca++ release but from Ca++ influx from outside the cells. The increased intracellular Ca++ concentrations stimulate Ca++/calmodulin (CaM)–dependent myosin light chain kinase to phosphorylate myosin light chain continuously during vasospasm. A topical application of genistein, ethylene-glycol-bis(β-aminoethylether) N,N'-tetraacetic acid, or various L-type Ca++ channel blockers likely induces reversal of vasospasm as a result of a decrease in intracellular Ca++ levels. The blood products also activate the rho/rho-associated kinase pathway during vasospasm most likely via G protein–coupled receptors, and the activated rho-associated kinase inhibits myosin phosphatase through phosphorylation at its myosin-binding subunit to induce Ca++-independent development of vasospasm. The enhanced generation of arachidonic acid during vasospasm may also contribute to inhibition of myosin phosphatase, at least in part, through the rho/rho-associated kinase pathway. The activity of myosin phosphatase in vasospam can also be inhibited by activated protein kinase C independently of the rho/rho-associated kinase pathway, but the inhibition may play a minor and transient role in contractile regulation. The protein levels of thin filament–associated proteins, calponin and caldesmon, are progressively decreased in vasospasm, whereas their phosphorylation levels are increased. Both changes probably contribute to the enhancement of smooth muscle contractility. Contractile and cytoskeletal proteins appear to be degraded in vasospasm by proteolysis with activated μ-calpain, suggesting that the intracellular devices responsible for smooth-muscle contraction are severely degraded in vasospasm. Conclusions It remains to be determined the extent to which Ca++-dependent and -independent contractile regulations, proteolysis and phosphorylation of thin filament–associated proteins, and degradation of contractile and cytoskeletal proteins are involved in the development of vasospasm.

scholarly journals Specific release of membrane-bound annexin II and cortical cytoskeletal elements by sequestration of membrane cholesterol.

1997 ◽  
Vol 8 (3) ◽  
pp. 533-545 ◽  
Author(s):  
T Harder ◽  
R Kellner ◽  
R G Parton ◽  
J Gruenberg
Keyword(s):  
Actin Cytoskeleton ◽  
Cytoskeletal Proteins ◽  
Annexin Ii ◽  
Dependent Manner ◽  
Cortical Actin ◽  
Independent Manner ◽  
Low Concentrations ◽  
Early Endosomes ◽  
Associated Proteins ◽  
Cytoskeletal Elements

Annexin II is an abundant protein which is present in the cytosol and on the cytoplasmic face of plasma membrane and early endosomes. It is generally believed that this association occurs via Ca(2+)-dependent binding to lipids, a mechanism typical for the annexin protein family. Although previous studies have shown that annexin II is involved in early endosome dynamics and organization, the precise biological role of the protein is unknown. In this study, we found that approximately 50% of the total cellular annexin was associated with membranes in a Ca(2+)-independent manner. This binding was extremely tight, since it resisted high salt and, to some extent, high pH treatments. We found, however, that membrane-associated annexin II could be quantitatively released by low concentrations of the cholesterol-sequestering agents filipin and digitonin. Both treatments released an identical and limited set of proteins but had no effects on other membrane-associated proteins. Among the released proteins, we identified, in addition to annexin II itself, the cortical cytoskeletal proteins alpha-actinin, ezrin and moesin, and membrane-associated actin. Our biochemical and immunological observations indicate that these proteins are part of a complex containing annexin II and that stability of the complex is sensitive to cholesterol sequestering agents. Since annexin II is tightly membrane-associated in a cholesterol-dependent manner, and since it seems to interact physically with elements of the cortical actin cytoskeleton, we propose that the protein serves as interface between membranes containing high amounts of cholesterol and the actin cytoskeleton.

Altered Cytoskeleton in Smooth Muscle of Aganglionic Bowel

2002 ◽  
Vol 126 (6) ◽  
pp. 692-696
Author(s):  
Laszlo Nemeth ◽  
Udo Rolle ◽  
Prem Puri
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Laser Scanning ◽  
Hirschsprung Disease ◽  
Muscle Cells ◽  
Cytoskeletal Proteins ◽  
Laser Scanning Microscopy ◽  
Confocal Laser ◽  
Normal Bowel ◽  
Pull Through

Abstract Context.—Intestinal motility is under the control of smooth muscle cells, enteric plexus, and hormonal factors. In Hirschsprung disease (HD), the aganglionic colon remains spastic or tonically enhanced and unable to relax. The smooth muscle cell's cytoskeleton consists of proteins or structures whose primary function is to link or connect protein filaments to each other or to the anchoring sites. Dystrophin is a subsarcolemmal protein with a double adhesion property, one between the membrane elements and the contractile filaments of the cytoskeleton and the other between the cytoskeletal proteins and the extracellular matrix. Desmin and vinculin are functionally related proteins that are present in the membrane-associated dense bodies in the sarcolemma of the smooth muscle cells. Objective.—To examine the distribution of the cytoskeletal proteins in the smooth muscle of the aganglionic bowel. Design.—Bowel specimens from ganglionic and aganglionic sections of the colon were collected at the time of pull-through surgery from 8 patients with HD. Colon specimens collected from 4 patients at the time of bladder augmentation acted as controls. Anti-dystrophin, anti-desmin, and anti-vinculin antibodies were used for fluorescein immunostaining using confocal laser scanning microscopy. Results.—Moderate to strong dystrophin immunoreactivity was observed at the periphery of smooth muscle fibers in normal bowel and ganglionic bowel from patients with HD, whereas dystrophin immunoreactivity was either absent or weak in the smooth muscle of aganglionic colon. Moderate to strong cytoplasmic immunostaining for vinculin and desmin was seen in the smooth muscle of normal bowel and ganglionic bowel from patients with HD, whereas vinculin and desmin staining in the aganglionic colon was absent or weak. Conclusion.—This study demonstrates that the cytoskeletal proteins are abundant in the smooth muscle of normal bowel, but are absent or markedly reduced in the aganglionic bowel of HD. As cytoskeletal proteins are required for the coordinated contraction of muscle cells, their absence may be responsible for the motility dysfunction in the aganglionic segment.

Abstract 17084: Nuclear Smooth Muscle α-actin Participates in Chromatin Remodeling at Smooth Muscle Contractile Gene Promoters

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Callie Kwartler ◽  
Shuangtao Ma ◽  
Caroline Kernell ◽  
Xue-yan Duan ◽  
Charis Wang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Cardiac Muscle ◽  
Chromatin Remodeling ◽  
Muscle Cells ◽  
Cytoskeletal Proteins ◽  
Nuclear Localization Sequence ◽  
Serum Starvation ◽  
Cell Fractionation ◽  
Gene Promoters ◽  
Chromatin Remodeling Complexes

Actin genes encode for cytoskeletal proteins that polymerize to function in cellular motility, adhesion, and contraction. In mammalian cells, ubiquitously expressed β-actin also moves into the nucleus and associates with chromatin remodeling complexes, however a nuclear function of muscle-specific α-actins has not been previously assessed. We hypothesized that smooth muscle α-actin (SMA) plays a role in chromatin remodeling during the differentiation of smooth muscle cells (SMCs) to enable cell fate specification of SMCs. In explanted SMCs from human and mouse ascending aortas, cell fractionation and 2D gel electrophoresis identify both SMA and β-actin in the nuclear lysates. Nuclear SMA but not β-actin accumulates with SMC differentiation driven by serum starvation and transforming growth factor-β1 treatment. SMA accumulates into the nucleus early in the differentiation of SMCs from neural crest progenitor cells, prior to cytosolic accumulation. Immunoprecipitation studies show that SMA binds specifically to the INO80 and the SWI/SNF chromatin remodeling complexes, and this binding increases with SMC differentiation. Chromatin immunoprecipitation reveals that SMA is bound to the promoters of SMC-specific genes, including Acta2 , Cnn1, and Myh11 and that SMA is enriched over β-actin at these promoters with SMC differentiation. Finally, overexpression of SMA tagged with a nuclear localization sequence (NLS) in multiple cell types increases expression of SMC markers, whereas NLS-tagged β-actin localizes to the nucleus to the same extent but does not increase SMC marker expression in any cell type. Finally, we assessed whether skeletal muscle α-actin (SKA) and cardiac muscle α-actin (CMA) may play a similar role in skeletal and cardiac muscle cells. Both SKA and CMA translocate into the nucleus. CMA accumulates into the nucleus early in the differentiation of cardiomyocytes from pluripotent stem cells. Immunoprecipitation reveals that SKA binds to the SWI/SNF complex in differentiated C2C12 myotube cell cultures. These data support that nuclear SMA enriches with and participates in SMC differentiation, and suggest a potential nuclear role for other muscle specific α-actins in developing muscle cells.

Sign in / Sign up

Export Citation Format

Share Document