Dense bodies and actin polarity in vertebrate smooth muscle.

Bond, Meredith; Somlyo, Avril V.

doi:10.1083/jcb.95.2.403

Cited by 157 publications

(89 citation statements)

References 43 publications

(37 reference statements)

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“…Scatterplot depicts the mean ± SD (***P < 0.0001 by paired t test from two independent and blinded observers). Smooth muscle dense bodies are thought to act as anchor points bridging the actin cytoskeleton with thin filaments (32,33), suggesting that changes in dense body characteristics reported here uncouple the actin cytoskeleton from the contractile apparatus of visceral smooth muscle-containing organs such as stomach, intestine, and bladder of Lmod1 −/− mice. Further confirmation and characterization of visceral smooth muscle nemaline-like bodies is needed in other animal models of MMIHS, as well as MMIHS patients, to establish a pathological role of these intriguing structures.…”

Section: Discussionmentioning

confidence: 83%

Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice

Halim

Wilson

Oliver

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

106

108

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Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is a congenital visceral myopathy characterized by severe dilation of the urinary bladder and defective intestinal motility. The genetic basis of MMIHS has been ascribed to spontaneous and autosomal dominant mutations in actin gamma 2 (ACTG2), a smooth muscle contractile gene. However, evidence suggesting a recessive origin of the disease also exists. Using combined homozygosity mapping and whole exome sequencing, a genetically isolated family was found to carry a premature termination codon in Leiomodin1 (LMOD1), a gene preferentially expressed in vascular and visceral smooth muscle cells. Parents heterozygous for the mutation exhibited no abnormalities, but a child homozygous for the premature termination codon displayed symptoms consistent with MMIHS. We used CRISPR-Cas9 (CRISPR-associated protein) genome editing of Lmod1 to generate a similar premature termination codon. Mice homozygous for the mutation showed loss of LMOD1 protein and pathology consistent with MMIHS, including late gestation expansion of the bladder, hydronephrosis, and rapid demise after parturition. Loss of LMOD1 resulted in a reduction of filamentous actin, elongated cytoskeletal dense bodies, and impaired intestinal smooth muscle contractility. These results define LMOD1 as a disease gene for MMIHS and suggest its role in establishing normal smooth muscle cytoskeletal–contractile coupling.

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Section: Discussionmentioning

confidence: 83%

Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice

Halim

Wilson

Oliver

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

106

108

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“…1, the model of a contractile unit of smooth muscle consists of a side-polar thick filament (6) flanked by thin filaments of opposite polarity. The thin filaments are anchored to dense bodies that are believed to be the Z-disk equivalents in smooth muscle (4,11,26,42). Our recently reported findings suggest that dense bodies may not be the Z-disk Fig.…”

Section: Modelsmentioning

confidence: 90%

“…The row-polar thick filament suggested by Hinssen et al (20) could also work for the proposed contractile unit. Evidence for the dense bodies acting as anchorage sites for the thin filaments was provided by some early studies (4,11,26,42). A recent study (46) showed that dense bodies formed long cablelike structures within smooth muscle cells and were capable of bearing passive tension.…”

Section: Assumptions Associated With the Modelsmentioning

confidence: 99%

Time course of isotonic shortening and the underlying contraction mechanism in airway smooth muscle

Syyong

Raqeeb

Paré

et al. 2011

Journal of Applied Physiology

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Syyong HT, Raqeeb A, Paré PD, Seow CY. Time course of isotonic shortening and the underlying contraction mechanism in airway smooth muscle. J Appl Physiol 111: 642-656, 2011. First published June 2, 2011; doi:10.1152/japplphysiol.00085.2011.-Although the structure of the contractile unit in smooth muscle is poorly understood, some of the mechanical properties of the muscle suggest that a sliding-filament mechanism, similar to that in striated muscle, is also operative in smooth muscle. To test the applicability of this mechanism to smooth muscle function, we have constructed a mathematical model based on a hypothetical structure of the smooth muscle contractile unit: a side-polar myosin filament sandwiched by actin filaments, each attached to the equivalent of a Z disk. Model prediction of isotonic shortening as a function of time was compared with data from experiments using ovine tracheal smooth muscle. After equilibration and establishment of in situ length, the muscle was stimulated with ACh (100 M) until force reached a plateau. The muscle was then allowed to shorten isotonically against various loads. From the experimental records, length-force and force-velocity relationships were obtained. Integration of the hyperbolic force-velocity relationship and the linear length-force relationship yielded an exponential function that approximated the time course of isotonic shortening generated by the modeled sliding-filament mechanism. However, to obtain an accurate fit, it was necessary to incorporate a viscoelastic element in series with the sliding-filament mechanism. The results suggest that a large portion of the shortening is due to filament sliding associated with muscle activation and that a small portion is due to continued deformation associated with an element that shows viscoelastic or power-law creep after a step change in force. mathematical model; contractile unit; sliding-filament mechanism THE STRUCTURE OF THE CONTRACTILE unit in smooth muscle is unknown, despite the common belief that the cycling-crossbridge/sliding-filament mechanism of contraction, which operates in striated muscle, is also responsible for smooth muscle contraction. The predominant model for the sarcomere-equivalent contractile unit in smooth muscle is a side-polar myosin (thick) filament sandwiched by two oppositely oriented actin (thin) filaments, each attached to a dense body that is believed to function like a Z disk in striated muscle (18,21,27), as shown in Fig. 1. An important assumption associated with the model is that the sliding of the thick and thin filaments relative to each other is caused by repetitive interaction of the myosin heads (cross bridges) of the thick filament with the thin filaments, in the same manner described for striated muscle (22,23). Such a cross-bridge mechanism for smooth muscle myosin has been observed in experiments where the interaction of isolated individual myosin heads with thin filaments was visualized and quantified directly (14, 15, 28). As predicted by Huxley's 1957 model (22), the ...

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“…Electron dense areas are also observed in the smooth muscle cell cytoplasm that are referred to as "dense bodies". They are obliquely oriented elongated structures up to 1.5 mm in length that are distributed relatively uniformly throughout the cytoplasm [6,15,23,38]. Actin filaments appear in association with virtually all cytoplasmic dense bodies.…”

Section: Cellular Organization Of Contractile Apparatusmentioning

confidence: 99%

“…Actin filaments appear in association with virtually all cytoplasmic dense bodies. The decoration of actin filaments with myosin subfragments (S-1) indicates that the filaments are oriented with the right polarity for force generation (arrowheads pointing away from the dense bodies) [15,38]. The observation that actin filaments with opposite polarity extend from either side of a given dense body has led to the suggestion that the cytoplasmic dense bodies are functionally equivalent to the Z-bands of striated muscle.…”

Section: Cellular Organization Of Contractile Apparatusmentioning

confidence: 99%

The contractile apparatus and mechanical properties of airway smooth muscle

Gunst¹,

Tang²

2000

Eur Respir J

146

122

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The functional properties of airway smooth muscle are fundamental to the properties of the airways in vivo. However, many of the distinctive characteristics of smooth muscle are not easily accounted for on the basis of molecular models developed to account for the properties of striated muscles. The specialized ultrastructural features and regulatory mechanisms present in smooth muscle are likely to form the basis for many of its characteristic properties.The molecular organization and structure of the contractile apparatus in smooth muscle is consistent with a model of force generation based on the relative sliding of adjacent actin and myosin filaments. In airway smooth muscle, actomyosin activation is initiated by the phosphorylation of the 20 kDa light chain of myosin; but there is conflicting evidence regarding the role of myosin light chain phosphorylation in tension maintenance. Tension generated by the contractile filaments is transmitted throughout the cell via a network of actin filaments anchored at dense plaques at the cell membrane, where force is transmitted to the extracellular matrix via transmembrane integrins. Proteins bound to actin and/or localized to actin filament anchorage sites may participate in regulating the shape of the smooth muscle cell and the organization of its contractile filament system. These proteins may also participate in signalling pathways that regulate the crossbridge activation and other functions of the actin cytoskeleton.The length-dependence of active force and the mechanical plasticity of airway smooth muscle may play an important role in determining airway responsiveness during lung volume changes in vivo. The molecular basis for the length-dependence of tension in smooth muscle differs from that in skeletal muscle, and may involve mechano-transduction mechanisms that modulate contractile filament activation and cytoskeletal organization in response to changes in muscle length. The reorganization of contractile filaments may also underlie the plasticity of the mechanical response of airway smooth muscle. Changes in the structural organization and signalling pathways of airway smooth muscle cells resulting form alterations in mechanical forces in the lung may be important factors in the development of pathophysiological conditions of chronic airway hyperresponsiveness. Eur Respir J 2000; 15: 600±616. The mechanical properties of airway smooth muscle are fundamental to the regulation of airway contractility and airway tone in vivo. These mechanical properties have traditionally been interpreted in terms of the "sliding filament model" of muscle contraction first proposed by HUXLEY and NIEDERGERKE [1] and HUXLEY and HANSON [2] to explain the contractile behaviour of skeletal muscle. Like other smooth muscles, airway smooth muscle exhibits the same hyperbolic force-velocity relationship that is characteristic of striated muscles, and the lengthtension relationship is also qualitatively similar to that of striated muscles [3]. The qualitative similarities be...

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Dense bodies and actin polarity in vertebrate smooth muscle.

Cited by 157 publications

References 43 publications

Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice

Loss of LMOD1 impairs smooth muscle cytocontractility and causes megacystis microcolon intestinal hypoperistalsis syndrome in humans and mice

Time course of isotonic shortening and the underlying contraction mechanism in airway smooth muscle

The contractile apparatus and mechanical properties of airway smooth muscle

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