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The Proceedings of the American Thoracic Society 5:40-46 (2008)
© 2008 The American Thoracic Society
doi: 10.1513/pats.200704-053VS
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Molecular Mechanics of Smooth Muscle Contractile Proteins in Airway Hyperresponsiveness and Asthma

Renaud Léguillette1 and Anne-Marie Lauzon2

1 University of Calgary, Faculty of Veterinary Medicine, Calgary, Alberta, Canada; and 2 Meakins-Christie Laboratories, McGill University, Montréal, Québec, Canada

Correspondence and requests for reprints should be addressed to Anne-Marie Lauzon, Ph.D., Meakins-Christie Laboratories, McGill University, 3626 St-Urbain street, Montréal, PQ, H2X 2P2 Canada. E-mail: anne-marie.lauzon{at}mcgill.ca

ABSTRACT

Airway hyperresponsiveness (AH) is a hallmark of asthma. The dynamics of the airway smooth muscle (SM) contraction, rather than its force-generating capacity, have been postulated to be key features of AH. Two mechanisms were proposed whereby an increased velocity of shortening (Vmax) of the airway SM leads to excessive bronchoconstriction. The first mechanism involves a greater Vmax during the initial portion of contraction, whereas the second mechanism implicates a greater Vmax after muscle stretches, such as after each tidal breath. This review focuses on the components of the contractile apparatus that have so far been reported to enhance the mechanics of the myosin molecular motor, thus leading to a greater Vmax. A greater activation of myosin, via increased phosphorylation of its regulatory light chain (LC20) by myosin light chain kinase, correlates with an increased Vmax in models of AH and in human asthmatic bronchial SM cells. However, poor correlations between these two parameters have also been reported in other models. A greater expression of the fast SM myosin heavy chain isoform [(+)insert or SM-B] also correlates with the greater Vmax measured in models of AH and in human asthmatic bronchial SM cells. However, the (+)insert isoform can only explain a twofold increase in Vmax, as extrapolated from its velocity of actin filament propulsion in the in vitro motility assay. Further considerations are given to the combination of these two factors with other components of the contractile machinery, thereby leading to the enhancement of airway SM function.

Key Words: thin filament • thick filament • myosin • actin • phosphorylation

The role of smooth muscle (SM) in normal airways is not clear (1, 2) but it is widely accepted that its function is altered in asthma (3). Asthmatic airways exhibit two distinctive abnormalities that can be at least partly attributed to SM dysfunction. First, patients with asthma show bronchial hyperresponsiveness, which is the occurrence of excessive bonchoconstriction in response to a given dose of agonist. This is also reflected in a fall in forced expiratory volume in 1 second (FEV1) that occurs at much lower doses of agonists than in normal subjects, and in an agonist dose–response curve that shows no maximum or plateau (4). A second feature of asthma, that is likely due to abnormalities in SM, is the inability of deep inspirations to reverse acutely induced bronchoconstriction (5), and in some cases to even worsen the symptoms (6). Although it is now accepted that airway SM mass is increased in fatal asthma, it may not be the case for nonfatal asthma. Indeed, using techniques that allow the distinction between smooth muscle cells and extracellular matrix, Thomson and coworkers reported no differences in smooth muscle mass between subjects with asthma and control subjects (7, 8). Thus, alterations in properties intrinsic to the SM most probably explain the abnormalities of airway constriction in asthma.

Intuitively, a stronger muscle should lead to a greater extent of shortening in response to a contractile stimulus, and to a greater airway narrowing. Thus, force generation in response to agonist stimulation was the first mechanical parameter of SM to be tested with respect to airway responsiveness. Surprisingly, there was no consensus attained among studies and it was concluded that isometric force is not different between asthmatic and normal airway SM (9–12). However, the difficulty in reporting force measurements relative to optimal length and normalized to SM volume or mass should be taken into account when reviewing this literature. Despite those limitations, it has been generally accepted that bronchial SM contractility is unchanged in asthma and that bronchospasms probably result from excessive stimulation. More recently, however, the dynamic behavior (velocity of shortening) of airway SM was suggested to be a key feature of the exaggerated airway narrowing observed in asthma. This proposal followed the multiple reports of the increased velocity of SM shortening (Vmax) observed in airway hyperresponsiveness and asthma. That is, a greater Vmax has been observed ex vivo in airways of the allergic dog model (13, 14) and allergic mouse model (15) stimulated electrically, in innate airway hyperresponsiveness in mouse stimulated with metacholine (16) and in rats stimulated electrically (17) or with metacholine (18), in sensitized human bronchi (19), and in single SM cells from asthmatic human bronchi (20) stimulated electrically.

Two mechanisms have been suggested to explain how an increased Vmax could lead to airway hyperresponsiveness. The first theory emerged from the measurements performed by Stephens and coworkers, who showed in their allergic dog model that the development of Vmax occurs during the first 2 seconds of a 10-second contraction (14, 21). They suggested that the remaining of the contraction was handled by more slowly cycling cross-bridges, so-called latch-bridges. Similarly, they showed in human bronchial SM cells that 90% of the shortening occurs during the first 1.5 seconds of the contraction (20). From those observations, they suggested that a faster contractile machinery would lead to a greater extent of shortening during the first few seconds of active contraction, thus a greater airway narrowing (14, 21). The second theory suggested to explain how a greater Vmax could lead to airway hyperresponsiveness emerged from the more recent advances on the effects of deep inspiration. When subjects without asthma are prevented from taking deep breaths, they experience airway hyperresponsiveness similar to that of subjects with asthma (22). Thus, it has been hypothesized that airway SM stretching by tidal inflation or deep breaths decrease airway resistance in normal lungs but not in those of patients with asthma (5, 22). Modern imaging techniques have revealed that airways of patients with asthma also dilate upon stretching but that this dilation is transient, as asthmatic airways quickly narrow back to their initial diameter (23). These results suggest that asthmatic airway SM can shorten faster than normal SM after a stretch. This rapid reconstriction might maintain asthmatic airway SM in a more constricted state because it would have time to shorten significantly between each breath, which would counteract the relaxing effect of tidal breathing (24, 25). Indeed, it is thought that the degree of airway narrowing is an equilibrium state that depends on the rate of acto-myosin cross-bridge interaction versus the rate of stretch imposed on airway SM by tidal breathing (26). Therefore, a greater rate of SM shortening is more likely to compensate for the disruptions of the cross-bridges induced by oscillatory stretches (24–27).

The proteins of the contractile apparatus are responsible for force and movement of muscle and dictate the resulting mechanical properties of the airway SM. Therefore, this article will focus on the molecular mechanics of the proteins of the contractile apparatus in the context of asthma and airway hyperresponsiveness. Specifically, we will address the expression and function of the various contractile proteins found in airway SM.

PROTEINS OF THE CONTRACTILE APPARATUS

The SM contractile apparatus is composed of thick and thin filaments. The thick filaments are constituted of myosin molecules, while the thin filaments comprise {alpha}– and {gamma}–actin; the regulatory proteins tropomyosin, caldesmon and calponin; and potentially, SM22 (Figure 1). There would be no movement possible without the molecular motor myosin. Molecular motors are mechanoenzymes that can transform the chemical energy liberated from ATP hydrolysis into mechanical work. Myosin is a hexameric protein made up of two heavy chains (~ 200 kD), each noncovalently associated with a pair of light chains, the essential (17 kD) and the regulatory (20 kD) light chains (Figure 2) (28–30).


Figure 1
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  		Figure 1. Smooth muscle myosin thick filament composed of myosin heavy chains and light chains (essential and regulatory) and thin filament composed of actin, tropomyosin, caldesmon, and calponin. P: phosphorylated myosin head. Modified by permission from Reference 108.

 

Figure 2
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  		Figure 2. Schematic illustrating the structure of the smooth muscle myosin heavy and light chains. The insert is shown in red. The (–)insert loop is shown in blue like the rest of the heavy chain. The regulatory light chain is shown in yellow and the essential light chain is shown in pink. The model was generated using the coordinates of Rayment (107) using Insight 2, v. 95.0 (MSI; San Diego, CA). Modified by permission from References 53, 109, 110.

 
Smooth Muscle Myosin Heavy Chains
The head, or the N-terminus, of the SM myosin heavy chain (SMMHC) contains the ATP and the actin-binding domains (Figure 2). The tail, or the C-terminus, of the SMMHC forms an elongated coiled-coil {alpha}-helix involved in self-association and thick-filament formation (Figure 2) (31). There are four known isoforms of the SMMHC that are generated by alternative splicing of a single gene located on chromosome 16p13.13–13.12 in humans (32). At the C-terminus, the isoforms differ by distinct sequences of 43 (SM-1) or 9 (SM-2) amino acids yielding a longer (204 kD) and a shorter (200 kD) tailed myosin, respectively (33, 34). The shorter sequence of SM2 results from the insertion of an exon that encodes a stop codon (Figure 3) (35, 36). The SMMHC assembles as dimers and although SM-1 and SM-2 heterodimers can be cross-linked in vitro, cells seem to preferentially contain homodimers (31). The content of SM-1 and SM-2 varies with tissues and was shown in many species to shift during maturation of SM cells (37, 38). However, there are no differences in SM-1 and SM-2 expression between human adult and infant bronchial or tracheal tissue (39). It is also believed that the expression of the SM-1 and SM-2 isoforms is not altered in asthma (40). Nonetheless, the function of SM-1 and SM-2 is still unclear. Indeed, no differences were observed in their velocity of actin filament propulsion ({nu}max) as measured by the in vitro motility assay (31, 41) or in the Vmax measured in tissues with different SM-1:SM-2 content (42–44). However, the filament assembly of SM-1 and SM-2 differ in vitro (31), which might confer functional differences at the whole muscle level. This will require further investigation.


Figure 3
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  		Figure 3. Schematic illustrating the alternative splicing of the mRNA that occurs in SMMHC at the 5' and 3' ends. Inclusion of exon 5b generates the (+)insert isoform, whereas inclusion of exon 41, encoding a stop codon, generates the shorter (200-kD) SM2 isoform. The amino acid sequence of the insert is indicated for human myosin. Modified by permission from References 50 and 109.

 
At the N-terminus, two SMMHC isoforms are generated by alternative splicing of a 21–base pair exon, between exon 5a and exon 6 (Figures 2 and 3) (45, 46). These isoforms differ by the presence [(+)insert] or absence [(–)insert] of a 7–amino acid insert in the flexible surface loop 1. The (+) and (–)insert SMMHC isoforms are also commonly referred to as SM-B and SM-A, respectively. The expression of (+) and (–)insert isoforms is tissue specific. Indeed, studies have shown, at both the mRNA and protein levels, that the rapidly contracting phasic muscle expresses more of the (+)insert isoform, whereas the slowly contracting tonic muscle expresses more of the (–)insert isoform (47–49). The human (+)insert isoform sequence was recently determined and confirmation was obtained of its greater expression in human phasic than tonic SM, while the levels in the trachea were intermediate (50). There is growing interest in the study of these N-terminus isoforms because the sole addition of the 7–amino acid insert alters drastically the myosin molecular mechanics.

In addition to a twofold greater ATPase activity, the (+)insert isoform has a twofold greater {nu}max than the (–)insert isoform (51–53). This has been further dissected using a laser trap assay to measure the force and displacement generated by single myosin molecules. Whereas both myosin isoforms produced similar unitary force and displacement, the presence of the insert decreased the attachment time to actin after the power stroke by approximately twofold (53). The net effect of this decrease in time of attachment of myosin to actin is to increase the cross-bridge cycling rate. Furthermore, it was shown that both the time of MgADP release and the time for MgATP binding were decreased in presence of the insert (53). Thus, the insert in loop 1 controls the rate of MgADP release, which is itself the rate-limiting step of unloaded Vmax (54, 55). How exactly the insert acts is still unknown, but it has been suggested that its presence increases the flexibility of the loop above the nucleotide-binding pocket, which facilitates the in and out movement of the nucleotides (56).

Smooth Muscle Myosin Light Chains
In SM, phosphorylation of the regulatory light chain LC20 is responsible for myosin activation (57) (Figure 2). This phosphorylation is accomplished by myosin light chain kinase (MLCK), which is itself activated by the calcium–calmodulin complex. Dephosphorylation is accomplished by myosin light chain phosphatase (MLCP). Experiments using the in vitro motility assay have shown that there is no movement without myosin LC20 phosphorylation (58). There are two isoforms of the LC20, but no functional differences are known between them. The role of the essential light chain LC17, on the other hand, is still poorly understood. It has been shown in skeletal muscle that removal of the LC17 decreases {nu}max as well as its molecular force generation, as measured in the micro-needle assay (59). Exactly how the LC17 exerts this function is unclear, but it is believed to strengthen the myosin lever arm (59). Two isoforms of the LC17 (LC17a and LC17b) are also generated from a single gene by alternative splicing of the mRNA (60–62). Any combination of the heavy and light chain isoforms is possible (Figure 3). Some studies have shown a preferential expression of the acidic LC17a isoform in conjunction with the (+)insert myosin heavy chain in rapidly contracting phasic muscle and of the basic LC17b isoform with the (–)insert myosin heavy chain in slowly contracting tonic muscle (61, 63, 64). However, other studies have shown a lack of correlation between contractility and LC17 isoform expression (61, 63, 65). More recently, uncorrelated expression of LC17 isoforms and SMMHC isoforms have been reported in animal models of airway hyperresponsiveness (66) and in bladder obstruction (67).

Because the discovery of the LC17 isoforms preceded that of the (+) and (–)insert SMMHC isoforms, it has been thought for a long time that the LC17 isoformic composition was an important determinant of the velocity of SM shortening. More recently, however, in an elegant study, Rovner and coworkers produced myosin molecules in which they exchanged the light chain isoforms and found that it was necessary and sufficient to express the insert in the heavy chain to double {nu}max (52). Furthermore, studies performed at the single cell level showed no correlation between LC17 isoform expression and the unloaded shortening velocity (43, 68). Altogether these results suggest that the SMMHC isoforms, rather than the LC17 isoforms, are the major determinants of the velocity of SM contraction.

Thin Filament Proteins
Filamentous actin is formed of a double-helix of polymers of globular actin. Contractile SM actin isoforms include the {alpha}– and {gamma}–isoforms, also referred to as vascular and enteric, respectively (69). The content in actin isoforms varies during development, but reaches a tissue-specific distribution in adults. These isoforms of actin have a very similar structure, differing only by four residues, mainly toward the N-terminus (70). The difference in function of the SM actin isoforms is poorly understood. Mice in which the {alpha}–SM actin gene had been knocked out showed abnormalities of vascular SM contraction and blood pressure regulation (71). Unfortunately, their airway SM function has not been studied. The role of the isoforms of actin does not seem to be mechanical because no difference is observed in {nu}max and in loaded velocity of actin propulsion in the in vitro motility assay, when exchanging SM actin for skeletal actin (72). They are, however, believed to be implicated in the regulation of contraction, along with the multiple actin decorating proteins.

The actin-binding proteins regulate the cross-bridge enzymatic and mechanical properties. Tropomyosin and caldesmon form continuous filaments that spiral around the actin double helices. Because of this continuous structure, they are though to transmit regulatory information to several myosin molecules simultaneously, allowing them to act cooperatively (reviewed in Reference 69). When bound to actin, tropomyosin is known to increase {nu}max (58), whereas caldesmon decreases both {nu}max and the myosin ATPase activity (58, 73). The inhibitory effect of caldesmon is thought to be reversed by the binding of Ca2+-calmodulin to caldesmon or by its phosphorylation (69). Caldesmon can also bind to actin via its N-terminus, but the function of this attachment remains unknown (reviewed in Reference 69). Similarly to caldesmon, calponin has been shown to inhibit myosin ATPase activity and to be regulated by phosphorylation (74). The function of calponin seems to be different depending on if it is in a phasic or a tonic muscle (75). Finally, SM22, which is ubiquitously expressed in SM, is also believed to be an actin binding protein, but its function remains unknown (76, 77). The expression and function of actin isoforms and all these actin regulatory proteins have been poorly addressed in airway hyperresponsiveness and asthma.

SMOOTH MUSCLE MOLECULAR AND TISSUE MECHANICS

Because myosin is the molecular motor that drives muscle contraction, it is not surprising that it has received enormous attention not only for its function in normal muscle mechanics, but also for its potential role in diseases. The remainder of this article will focus on the recent progress made in understanding the molecular and tissue mechanics of the SM myosin isoforms as well as their activation by MLCK.

Myosin Isoform Expression and Function in Health and in Models of Disease
A clear correlation between the (+)insert isoform expression and increased Vmax has been reported in rabbit vascular SM (78), in the opossum esophagus (64), and in the rabbit urinary system (79). At the cellular level, a clear relationship between the (+)insert content and Vmax has also been observed in the rabbit stomach, with the cells of the antrum expressing more of the (+)insert isoform and contracting at a faster Vmax than the cells from the fundus (80). In canine airways, a correlation between the (+)insert isoform expression and Vmax has also been reported, with the trachea expressing more of the (+)insert isoform and contracting to a greater extent and with a greater Vmax (81, 82). More recently, this relationship was also shown to be maintained at the molecular level. That is, myosin was purified from multiple rat organs and it was shown that the expression in (+)insert isoform and {nu}max were greater in the rapidly contracting phasic organs than in the slowly contracting tonic organs (50).

Many studies have shown that SMMHC isoform expression is altered in disease. This has been studied in models of bladder (reviewed in Reference 79) and intestinal obstruction (83), in models of pulmonary hypertension (84), as well as in models of asthma (66). The bladder and intestinal hypertrophic tissues showed decreases in (+)insert isoform expression along with decreases in rate of force development and Vmax, respectively (79). Furthermore, the changes observed in (+)insert expression in bladder hypertrophy, were shown to be due to changes in cell phenotype and not to the appearance of new cells (85). Treatment was shown to reverse the myosin isoform expression back to normal (86). Together these results demonstrate the ability of SM cells to adapt to their environmental conditions.

The expression of the (+)insert isoform was also addressed in the Fisher (F344) and Lewis rat model of airway hyperresponsiveness (66). A 44% greater expression in (+)insert relative to total SMMHC was found in the hyperresponsive Fisher rat trachea compared with the normoresponsive Lewis rat. This greater expression of the (+)insert isoform is in good agreement with the 46% greater Vmax of the Fisher rats measured at the muscle strip level (17), the greater rate of airway constriction measured in explants (18), and with preliminary data showing an approximately 20% greater {nu}max measured at the molecular level (87). At the whole animal level, the (+)insert isoform knockout mouse (88) exhibits an approximately 18% increase in time to peak airway resistance compared with the wild-type mice (89). Altogether these data highly suggest that the (+)insert isoform expression affects the velocity of airway SM shortening.

Myosin Activation in Health and in Models of Disease
Another factor that can affect airway SM shortening velocity is the level of activation of myosin light chain LC20. A greater level of phosphorylation has been associated with increased Vmax in a dog model of allergic airway hyperresponsiveness (21, 90). This greater phosphorylation level was due to a greater content in MLCK. This has also been studied in a model of innate airway hyperresponsiveness: the hyperresponsive Fisher F344 rats exhibit greater levels of phosphorylation of the LC20 than the Lewis rats (66) and this is also associated with a greater Vmax (17). A greater calcium mobilization was also observed in the F344 rats (91), thus leading to greater LC20 phosphorylation (66). However, the specific mechanism by which a greater phosphorylation level would enhance SM contractility remains unknown and controversial. For a given dose of agonist, a greater level of phosphorylation will lead to greater tension development (66). However, a clear link between phosphorylation level and Vmax remains to be established. Indeed, whereas multiple studies found a good correlation between myosin LC20 phosphorylation and Vmax (92–95), several others reported no correlation (96–99). The dissociation between Vmax and phosphorylation seems to be greatest early in the contraction in the case of tracheal smooth muscle (96).

Traditionally, greater levels of LC20 phosphorylation have been attributed to greater MLCK content but more recently the focus has turned to inhibition of MLCP (100). This mechanism is referred to as Ca2+ sensitization. This mechanism is regulated either directly by the monomeric protein RhoA and Rho-kinase or by phosphorylation of the MLCP inhibitor CPI-17 (100). Recent studies have demonstrated increased smooth muscle contractility due to Ca2+ sensitization in models of airway hyperresponsiveness (101, 102).

Myosin Activation and (+)Insert Isoform Expression in Human Asthma
Recent studies have addressed myosin activation in human asthmatic airway SM cells. An increased MLCK mRNA accompanied the greater Vmax and greater extent of shortening observed in mild asthmatic endobronchial single SM cells (20). Others used a morphometric analysis and reported an increase in MLCK protein level without changes in phosphorylated LC20 in individuals with severe asthma, but not in those with moderate asthma (103). It has also been shown that ex vivo sensitization of human airway SM increases the expression of MLCK (104). Furthermore, in another preliminary study, an increased MLCK mRNA was also observed in endobronchial biopsies from individuals with mild asthma (87). Altogether these studies strongly suggest that MLCK expression is increased in asthma. However, as mentioned above, the relationship between LC20 phosphorylation and Vmax has been challenged (96–99), so the role of MLCK in human airway hyperesponsiveness needs to be further addressed.

Because the human myosin isoforms have only recently been sequenced (50), and because of the difficulty in obtaining human bronchial tissues, the studies addressing the expression of the (+)insert isoform in human airways are only beginning. In a preliminary study, a 2.4-fold greater (+)insert myosin isoform mRNA expression was reported in individuals with mild asthma compared with control subjects (87). Given the correlations previously established between the (+)insert myosin isoform expression and {nu}max measured at the molecular level and Vmax measured at the muscle strip level, as well as its increased expression in several models of disease, the (+)insert isoform is likely to be one of the key contributors to airway hyperresponsiveness and asthma.

Future Directions
Multiple factors are likely to interact to enhance the contractile properties of asthmatic airway SM, and their role, alone and in conjunction, needs further investigation. Very little research has been done with respect to the potential involvement of the actin isoforms and actin regulatory proteins. One such example is SM22, which was recently shown to be increased by 2.2-fold at the mRNA level in bronchial biopsies from individuals with mild asthma (87). However, the mechanical function of SM22 remains completely unknown (105). It is even uncertain whether SM22 really acts as an actin-binding protein, although it is known to attach to actin. It is also uncertain whether its expression is exclusive to the SM cells (106). Furthermore, the implications of the various combinations of the head and tail myosin isoforms (SM-A and SM-B with SM-1 and SM-2), as well as the combinations with various light chain isoforms (LC17a and LC17b), still need to be assessed, and the functional impact in tissue will need to be weighted against regulation by LC20 phosphorylation. Obviously, more research is needed to address the function of all contractile proteins in normal contraction as well as in airway hyperresponsiveness and asthma. A major advancement will certainly come from the understanding of the mechanisms of regulation of the SMMHC isoform expression. Indeed, can factors such as inflammation, oxidative stress, and maturation regulate the alternative splicing of the SMMHC mRNA during health and disease? These issues have not been clarified, and thus future work is necessary.

CONCLUSIONS

Vmax has been shown to be increased in numerous models of airway hyperresponsiveness as well as in human asthma. A greater phosphorylation of the LC20 correlates with an increased Vmax in models of AH and in human asthmatic bronchial SM cells. However, a poor correlation between these two parameters has also been reported in other models. A greater expression of the fast (+)insert myosin isoform also correlates with the greater Vmax measured in models of AH and in human asthmatic bronchial SM cells. However, the contribution of the (+)insert isoform can be of at most a twofold increase in Vmax, as extrapolated from its velocity of actin filament propulsion in the in vitro motility assay. These two factors most probably combine to increase Vmax further. Clearly, more research is needed to determine if and how other parameters of the contractile apparatus also contribute to the enhancement of Vmax in airway hyperresponsiveness and asthma.

FOOTNOTES

Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form April 30, 2007; accepted in final form August 3, 2007)

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