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The Proceedings of the American Thoracic Society 5:62-67 (2008)
© 2008 The American Thoracic Society
doi: 10.1513/pats.200705-056VS
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Length Adaptation of Airway Smooth Muscle

Ynuk Bossé1,2, Apolinary Sobieszek3, Peter D. Paré1,4 and Chun Y. Seow1,2

1 The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, Providence Health Care/St. Paul's Hospital, and 2 Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada; 3 Institute for Biomedical Aging Research, Austrian Academy of Sciences, Innsbruck, Austria; and 4 Department of Medicine, University of British Columbia, Vancouver, Canada

Correspondence and requests for reprints should be addressed to Dr. Chun Y. Seow, Ph.D., iCAPTURE Centre/St. Paul's Hospital, Room 166, 1081 Burrard Street, Vancouver, BC, Canada, V6Z 1Y6. E-mail: cseow{at}mrl.ubc.ca

ABSTRACT

Many types of smooth muscle, including airway smooth muscle (ASM), are capable of generating maximal force over a large length range due to length adaptation, which is a relatively rapid process in which smooth muscle regains contractility after experiencing a force decrease induced by length fluctuation. Although the underlying mechanism is unclear, it is believed that structural malleability of smooth muscle cells is essential for the adaptation to occur. The process is triggered by strain on the cell cytoskeleton that results in a series of yet undefined biochemical and biophysical events leading to restructuring of the cytoskeleton and contractile apparatus and consequently optimization of the overlap between the myosin and actin filaments. Although length adaptability is an intrinsic property of smooth muscle, maladaptation of ASM could result in excessive constriction of the airways and the inability of deep inspirations to dilate them. In this article, we describe the phenomenon of length adaptation in ASM and some possible underlying mechanisms that involve the myosin filament assembly and disassembly. We discuss a possible role of maladaptation of ASM in the pathogenesis of asthma. We believe that length adaptation in ASM is mediated by specific proteins and their posttranslational regulations involving covalent modifications, such as phosphorylation. The discovery of these molecules and the processes that regulate their activity will greatly enhance our understanding of the basic mechanisms of ASM contraction and will suggest molecular targets to alleviate asthma exacerbation related to excessive constriction of the airways.

Key Words: cytoskeleton • contractile apparatus • airway constriction • asthma

Although the physiologic role played by airway smooth muscle (ASM) in regulating lung function is still debated (1–5), the muscle's role in asthma exacerbation is unambiguous: Exaggerated narrowing of the airways seen in acute asthma attacks is caused by excessive shortening of the ASM (1, 6). Asthma is a complex disease with multiple causes. However, the final common pathway that leads to the manifestation of symptoms is ASM contraction with an excessive amount of shortening (7). The mechanism underlying the abnormal ASM shortening and the resultant airway hyperresponsiveness seen in asthma is not known. It could be a result of increased ASM mass in the airways, an enhancement of contractility of individual cells, or both. It could also be a result of an altered airway environment that reduces the load imposed on the muscle, leading to unencumbered shortening and excessive constriction of the airways. Irrespective of the primary mechanism for airway hyperresponsiveness, length adaptation of the muscle to passively or actively shortened lengths has the capacity to further exacerbate the ASM shortening and narrowing of the airways (8–10). Understanding length adaptation is not only a crucial component for elucidating the basic mechanism of ASM contraction; it also aids identification of potential targets for intervention designed to prevent maladaptation and ASM dysfunction that cause asthma symptoms.

AIRWAY SMOOTH MUSCLE

In general, smooth muscle controls vital functions by regulating the physical dimension and mechanical property of hollow organs. Many of these organs (e.g., stomach and urinary bladder) regularly undergo large changes in volume, thus requiring the muscle cells lining the organ to have a large working length range. Although a large functional length range is not required for ASM, this muscle can generate maximal force over at least a threefold length range after length adaptation (11). Length adaptability (also known as mechanical plasticity) of ASM therefore imparts instability to airways in terms of their ability to maintain patency because of the possibility of airway closure due to smooth muscle being adapted to abnormally short lengths.

Evidence suggests that the ability of smooth muscle to generate force over a broad length range stems from the muscle's malleable myofilament lattice—a network of actin (thin), myosin (thick), and intermediate filaments—and the anchoring proteins that bind the filaments together. This newly recognized dynamic filament organization is thought to allow the muscle to adapt by optimizing contractile-filament overlap, such that the maximal force is maintained over the range of lengths needed for its physiologic function (1, 12–17). These recent conclusions suggest a new paradigm for smooth muscle contraction that has the potential to alter our approach to understand excessive airway narrowing. They also suggest that it is imperative that ASM research focuses on the regulation of organization (assembly) of structural proteins that are associated with cell malleability. The function of many proteins (some of them highly abundant) in smooth muscle is still unknown. The change in our view that emphasizes structural malleability and its regulation in smooth muscle cells may aid us in finding the real purposes for these proteins. Abnormal expression and/or function of these proteins may also represent novel therapeutic targets in diseases that involve altered structural and functional properties of smooth muscle cells.

THE PHENOMENON OF SMOOTH MUSCLE LENGTH ADAPTATION

The fixed-filament lattice limits striated muscle to generate maximal force within a length range of 10 to 20% of its resting length (18). This range is not adequate for most smooth muscles to carry out organ functions, such as emptying a urinary bladder or pushing out a fetus from a uterus. In many types of smooth muscle, maximal force generation is associated with a very broad length range, and the range becomes even broader if the muscle is allowed to adapt at each of the lengths where force measurements are made (8, 11). Length adaptation in smooth muscle can be induced by a single contraction (19, 20), a series of brief activations (11, 21), or a continuous submaximal activation (10) over a period of tens of minutes. Adaptation can also occur in a relaxed muscle set at a fixed length over a period of hours (8, 22) or days (9, 23, 24). Although acute and long-term length adaptation may have different mechanisms, results obtained with the various protocols seem to be the same: allowing the muscle to regain (at least partially) its ability to generate maximal force at the new length and causing a shift of the peak force of the bell-shaped "conventional" (nonadapted) active length-force curve toward the new length (Figure 1). The passive length–force curve also shifts with the active curve (8, 9). This mechanical plasticity extends the working length range of smooth muscle. Length adaptation is triggered by strain on the contractile apparatus and cytoskeleton (25) and is characterized by an initial phase during which partial disassembly of the contractile and cytoskeletal structures occurs, followed by a later phase, during which reassembly of the structures occurs at the new cell length (8, 26). The initial phase is often associated with a decrease in the muscle's active force and passive stiffness, whereas the later phase is associated with force and stiffness recovery (8). Impairment of the initial phase or enhancement of the later phase imparts instability to ASM in terms of its ability to regulate airway diameter. In the first case, failure of the muscle to respond to the initial trigger results in an airway nonresponsive to external strains (such as those induced by deep inspirations) that would otherwise lead to ASM relaxation. In the second case, because of the combined effects of the LaPlace Law (transmural pressure = wall tension/airway radius; i.e., a constricted airway will require less wall tension to maintain a certain transmural pressure) and increased muscle force (wall tension) due to adaptation, the likelihood of airway closure (even when the muscle is not maximally activated) will increase dramatically. However, length adaptation can be both detrimental and beneficial in terms of maintenance of airway patency. Adaptation of ASM to a longer length causes a shift of the length–force relationship to the right, reducing the amount of shortening against a constant load (27), and prevents excessive narrowing of the airways. This mechanism may underlie the observation made by Xue and colleagues (28) that airway responsiveness in rabbits in vivo is reduced by prolonged continuous positive airway pressure.


Figure 1
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  		Figure 1. Schematic illustration of a shift of active and passive length–force relationships based on data from Wang and colleagues (8). A smooth muscle adapted at an arbitrary reference length (Lref) produces a maximal isometric force at Lref (labeled "A"). The active and passive length–force relationships obtained without allowing the muscle to adapt to any length except Lref are illustrated by the solid curves. An acute shortening of the muscle by the amount of X (from Lref) reduces the force to that indicated by "B." If the muscle is allowed to adapt at the shortened length (Lref - X), isometric force recovers and reaches the same maximum before the shortening ("C"). The corresponding (nonadapted) active and passive length–force relationships (dotted curves) are also shifted by the same amount (X) as the maximal force. Vertical dotted lines indicate peak forces at Lref and Lref – X. Solid line connecting B and C and arrow indicate the magnitude and direction of force recovery after length change.

 
Although the maximal muscle force is largely independent of muscle length after adaptation, other properties, such as shortening velocity and muscle compliance, are highly length dependent (11, 26). A simple model that explains all these observations consists of contractile units arranged in series and in parallel (26, 27); adaptation of the muscle to different lengths involves adding or subtracting the units in series (Figure 2). Because a myosin filament is the central component of a contractile unit, any change in the number of contractile units inside a cell is accompanied by a corresponding change in the number of myosin filaments, possibly through polymerization or depolymerization. Furthermore, the change has to occur sufficiently rapidly to account for the observed swift time course of length adaptation (11, 25).


Figure 2
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  		Figure 2. Schematic illustration of length adaptation in smooth muscle. The model assumes that the number of contractile units in series is a linear function of the adapted muscle cell length. Lref = arbitrary reference length.

 
EVIDENCE FOR RAPID CONTRACTILE FILAMENT ASSEMBLY AND DISASSEMBLY IN INTACT SMOOTH MUSCLE

The underlying mechanism for the phenomenon of length adaptation in smooth muscle is not clear. The available evidence suggests that structural malleability of the network of contractile and cytoskeletal filaments is a key factor that gives the muscle the ability to adapt and function over a large length range (8, 11, 19, 25–27, 29–38). Studies reveal changes in the myosin-filament content in smooth muscle cells during contractile activation (39–41) and in its adaptation to different cell lengths (26, 32, 42). The content of actin filaments in smooth muscle has also been found to be variable: The filament content increases during contractile activation (32, 43). It seems, therefore, that the content of contractile filaments in smooth muscle can change rapidly, sometimes within seconds (42). The rapidity confers feasibility to the proposed models (Figure 2) based on myosin filament evanescence (26, 27) and suggests that rapid filament formation and dissolution in smooth muscle cells is governed by an equilibrium between nonfilamentous and filamentous myosin. In ASM cells adapted to a stretched length, we have observed a substantial increase in myosin filament content (26). We have proposed that this increase is due to additional contractile units incorporated into the contractile apparatus during the process of length adaptation. The observed increases in muscle power output (26), rate of ATP consumption (26), and shifts in the length–force relationship (27) also agree with this explanation (Figure 3). These observations suggest that the structural basis of smooth muscle contraction is not static akin to that of striated muscle but is dynamic and possesses many features of nonmuscle motile cells (16, 17).


Figure 3
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  		Figure 3. Mechanical and metabolic properties of smooth muscle as functions of adapted muscle length in airway smooth muscle. Based on the conceptual model shown in Figure 2, the shortening velocity and power output of the muscle is predicted (and verified by Pratusevich and colleagues [11] and Kuo and colleagues [26]) to be a linear function of the adapted muscle length (solid line). The rate of ATP use (solid circle) and myosin filament content (open circle) at different adapted muscle cell lengths obey the same linear relationship (26), thus supporting the basic assumption on which the model (Figure 2) is based.

 
POSSIBLE MECHANISMS REGULATING MYOFILAMENT ORGANIZATION AND LATTICE MALLEABILITY

Myosin filaments of smooth muscle are not stable and can be dissociated in solution at physiologic levels of MgATP, ionic strength, and pH, and phosphorylation of the regulatory myosin light chain (ReLC) stabilizes the filaments (44). Assembly of nonphosphorylated myosin monomers into filaments in solution has been found to be dependent on the monomer concentration; once a critical concentration is reached, self-assembly occurs (45). For a wide range of ionic strength, this critical concentration increases dramatically when ATP is present in the solution (45) and decreases when ReLC is phosphorylated (45, 46). The relevance of these in vitro mechanisms to intact smooth muscle cells is still a question. Based on these observations, at physiologic levels of MgATP, ionic strength, and pH and in the absence of ReLC phosphorylation, there should be few (if any) thick filaments formed in solution (47). Unfacilitated self-assembly of nonphosphorylated monomers into thick filaments in vivo is therefore not likely. The fact that thick filaments are found in relaxed smooth muscle cells suggests that there are other factors contributing to the thick filament formation in vivo. In intact ASM, we tested the idea that phosphorylation of ReLC may facilitate thick filament formation. By applying large amplitude length oscillation to relaxed trachealis muscle strips, we observed that thick filaments could be partially disassembled (25) (Figure 4). Reassembly of the filaments occurred when the muscle was repeatedly activated and relaxed in the absence of mechanical perturbation (25). However, this thick filament reassembly was prevented when phosphorylation of ReLC was inhibited (48). The results suggest that phosphorylation of ReLC is as important for thick filament formation in vivo as it is in vitro (47).


Figure 4
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  		Figure 4. Time course of recovery (adaptation) of isometric force and myosin filament content in airway smooth muscle after length perturbation (a 5-min sinusoidal length oscillation with a frequency of 0.5 Hz and 30% strain amplitude). The arrow indicates cessation of length perturbation. Isometric force was measured from brief tetani (12-second duration) induced by electrical field stimulation. Thick filament density was measured from cell cross-sections using electron microscopy after fixing the muscle at the indicated time points. Reference values were those obtained before length perturbation. Modified by permission from Reference 25.

 
A critical question is why are there so many thick filaments present in intact smooth muscle in the relaxed state when there is no ReLC phosphorylation (48). A possible answer is that the actin filament network plays a crucial role in guiding and facilitating thick filament formation. In vitro experiments (49, 50) suggest that this is possible; however, it needs to be validated in vivo. Caldesmon (an actin filament–associated protein) has also been shown to promote myosin filament formation in vitro (51); this needs to be verified by in vivo experiments. Telokin that modulates myosin phosphorylation rate (52) is likely involved in the filament assembly process (53, 54), but the mechanisms need to be elucidated. Other proteins, such as 38k protein (55), could contribute to the maintenance of thick filaments in the relaxed smooth muscle. These findings suggest that many proteins present in smooth muscle have the potential to preserve thick filaments in vivo, a role that was not considered important or necessary until recently.

For a contractile apparatus to function properly and generate force, thick filaments have to be placed in a lattice of thin filaments where they can interact with thin filaments possessing the appropriate polarities. Perhaps it is for this reason that many thick filament-stabilizing proteins are part of the thin filament network. These proteins are likely placed in specific areas of the thin filament network, and their locations determine where the thick filaments are formed. Caldesmon, for example, is found interspersed in the thin filament network where myosin filaments are also found (56, 57).

The structure and polarity of the actin filaments in smooth muscle has been well described (see Reference 58), but the same cannot be said for myosin filaments. An important feature of the thick filaments assembled in vitro is the absence of a central cross-bridge free (bare) zone seen in thick filaments from skeletal muscle (59). Instead, the thick filaments of smooth muscle showed asymmetrical cross-bridge free edges at their two ends (60). On the basis of these observations, a bipolar building unit made up of antiparallel myosin dimers was proposed. A more detailed model of the assembly of such dimers into a helical filament was subsequently described (61), emphasizing a major future of mixed polarity of the cross-bridges. In this model, myosin heads with the same polarity are lined up in a row extending helically from one end of the filament to the other, with the neighboring rows having the opposite polarity. The bipolar dimeric building unit has been incorporated into another model of smooth muscle myosin filaments (face polar model) that is based on observations of flat filaments with myosin heads possessing the same polarity on one side of the filament and those with opposite polarity on the other side (62). Both types of filament model will work (in theory) in contractile units such as those shown in Figure 2, but the frequent observation of myosin filaments surrounded by rosettes of actin filaments in smooth muscle favors the helical thick filament model.

This article focuses on the regulation of myosin filaments. Contraction of smooth muscle is primarily regulated by G-protein–coupled receptors and their associated signaling pathways that lead to the activation and reorganization of not only the myosin filaments, but also the actin filament lattice (actin cytoskeleton). Length adaptation in smooth muscle can only occur when both myosin- and actin-associated ultrastructures undergo plastic reorganization. The actin aspects of smooth muscle adaptation are reviewed by other articles in this virtual symposium.

It seems that lability of myosin filaments in smooth muscle, especially in the relaxed (nonphosphorylated) state, is a crucial property that allows the muscle to adapt to changes in configuration of the thin filament lattice, brought about by external and internal strains that change the cell dimension. The mechanical strains that shape the filament lattice also result in disassembly of the unphosphorylated thick filaments. Unraveling the molecular processes of the thick filament disassembly and subsequent reassembly during the course of length adaptation is critical to our understanding of normal smooth muscle function and its alteration in disease.

MALADAPTATION OF ASM AS A MAJOR CAUSE FOR ASTHMA EXACERBATION: A HYPOTHESIS

Before the discovery of the adaptation phenomenon in smooth muscle, shortening of the muscle from its "optimal" length was thought to be associated with a diminished ability for the muscle to generate force. Now that we know that adaptation allows smooth muscle to recover part (if not all) of its maximal force producing capacity after a length change, our view has changed regarding how airway caliber is controlled by the balance of muscle force and load. Because adaptation occurs most effectively under static conditions, the mechanically dynamic lung environment is probably the most important factor that prevents length adaptation of ASM from occurring and the ensuing excessive narrowing of the airways. If the airways are uncoupled from the lung parenchyma due to a loss of effective tethering or overly stiff airways (the latter could be due to an alteration in the mass or intrinsic properties of ASM or a change in the properties of the airway wall), a pernicious cycle could set in and lead to excessive narrowing or even closure of the airways. Adaptation of ASM leads to continued narrowing of the airways if there is no intervention (such as a length perturbation on the smooth muscle induced by a big breath in a healthy lung) to break up the cycle of length adaptation (Figure 5).


Figure 5
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  		Figure 5. Illustration of how length adaptation could lead to excessive shortening of airway smooth muscle. (A) A hypothetical load (against which the airway smooth muscle shortens) as a function airway radius. Ro is the radius before airway constriction. The curve labeled "{alpha}" represents the load stemming from the transmural pressure, according to the LaPlace Law (assuming a constant pressure). The curve labeled "β" represents the load stemming from parenchymal tethering and resistance from folding of lamina propria-submucosal layer as a function of airway radius. The total load "seen" by the muscle is ({alpha} + β). (B) The total load ({alpha} + β) is duplicated. The two solid lines represent length–force relationships of smooth muscle adapted to two lengths (from Herrera and colleagues [27]). Point "a" represents maximal isometric force of muscle adapted at Ro. When the muscle is stimulated to contract, it shortens following the instantaneous length–force curve (arrows) until the load equals the force at point "b." If the muscle is allowed to adapt at the shortened length, its ability to generate force increases with time and eventually reaches point "c." If the muscle is then stimulated again, it will shorten, following a new instantaneous length–force curve to reach point "d." The process can repeat itself and lead to excessive constriction of the airway.

 
CONCLUSIONS

Although length adaptation in smooth muscle is essential for physiologic function of many hollow organs that undergo large changes in volume, it could be a source of instability for the airways in terms of maintenance of airway patency. In vitro experiments have clearly demonstrated the phenomenon of length adaptation in ASM and its ability to shorten to such a length that would result in complete airway closure. However, in vivo observations in healthy lungs suggest that such harmful adaptation does not occur and that what prevents such adaptation from occurring is perhaps the constant agitation on ASM by the dynamic lung environment. A loss of this mechanical perturbation coupled with length adaptation could underlie the pathogenesis of many obstructive airway diseases such as asthma.

FOOTNOTES

Supported by operating grants from Canadian Institutes of Health Research (MOP-13271, MOP-4725).

Conflict of Interest Statement: Y.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. P.D.P. is the principle investigator of a project funded by GlaxoSmithKline to develop CT-based algorithms to quantitate emphysema and airway disease in chronic obstructive pulmonary disease. With collaborators he has received approximately $300,000 to develop and validate these techniques. He has applied funds solely to the research to support programs and technicians. He is also principal investigator of a Merck Frosst–supported research program to investigate gene expression in the lungs of patients who have chronic obstructive pulmonary disease. He and collaborators have received approximately $200,000 for this project. These funds have supported the technical personnel and expendables involved in the project. C.Y.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form May 3, 2007; accepted in final form May 29, 2007)

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