J Appl Physiol 110: 1130–1135, 2011.
First published December 2, 2010; doi:10.1152/japplphysiol.01192.2010.
Review
HIGHLIGHTED TOPIC
Emergent Behavior in Lung Structure and Function
Emergence of airway smooth muscle functions related to structural
malleability
Chun Y. Seow1 and Jeffrey J. Fredberg2
1
Department of Pathology, James Hogg Research Centre, University of British Columbia, Vancouver, British Columbia,
Canada; and 2Program in Molecular and Integrative Physiological Sciences, Department of Environmental Health, Harvard
School of Public Health, Boston, Massachusetts
Submitted 5 November 2010; accepted in final form 22 December 2010
length adaptation; cytoskeletal dynamics; contractile filaments; evanescence; dense
body; dense plaque
IF LIFE IS A COLLECTIVE PROPERTY of actively interacting molecules (43), then the same can be said about smooth muscle
function. Smooth and striated muscles share many common
properties; both tissues are highly specialized to generate force
and perform associated mechanical functions. However, many
of the emergent behaviors of smooth muscle differ dramatically from those of striated muscle. The most noticeable
differences have to do with malleability of the contractile
apparatus and supporting cytoskeletal scaffolding. From the
need to adapt to large and frequent changes in cell dimensions,
smooth muscle appears to have evolved a remarkable malleability that is readily modifiable by both mechanical and chemical stimuli. As a result of this malleability, the dynamic
mechanical properties of the cell have no characteristic scales
of length or time. Even the classical concept of optimal muscle
length is now understood to be largely a myth and has been
replaced by the concept of length adaptation.
In this minireview, the known emergent behaviors of smooth
muscle relating to structural malleability are described, although the specific molecular interactions that give rise to these
emergent behaviors remain largely unknown. However, some
Address for reprint requests and other correspondence: C. Y. Seow, James
Hogg Research Centre/St. Paul’s Hospital, 1081 Burrard St., Rm. 166, Vancouver, BC, Canada V6Z 1Y6 (e-mail: [email protected]).
1130
known properties of the elementary structures of smooth muscle, such as the contractile and cytoskeletal filaments, are
thought to contribute to these emergent behaviors; the properties of these elementary structures are discussed in the second
half of the review. Although this review is based on literature
in the area of airway smooth muscle (ASM), the phenomena
and behaviors described here are not unique to ASM and are
common with many types of smooth muscle and nonmuscle
cells.
RESPONSE OF ASM TO MECHANICAL PERTURBATION
Length adaptation. The characteristic relationship between
active force and sarcomere length in striated muscle can be
traced back to the interaction of myosin cross bridges with
actin filaments and the length dependence of that interaction
within the sarcomere (14). Because the exact structure of the
contractile unit in smooth muscle (akin to the sarcomere in
striated muscle) is not known, the length-force relationship of
smooth muscle cannot be linked to specific structures within
the contractile unit. The length-force relationship of smooth
muscle likely stems from interactions of myosin cross bridges
with actin filaments (18), as in striated muscle. However, the
emergent length-force properties of these two types of muscle
are different, as shown in Fig. 1A, suggesting that the lengthdependent cross-bridge interaction with actin filaments is dif-
8750-7587/11 Copyright © 2011 the American Physiological Society
http://www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.32.247 on June 17, 2017
Seow CY, Fredberg JJ. Emergence of airway smooth muscle functions related
to structural malleability. J Appl Physiol 110: 1130 –1135, 2011. First published
December 2, 2010; doi:10.1152/japplphysiol.01192.2010.—The function of a complex system such as a smooth muscle cell is the result of the active interaction
among molecules and molecular aggregates. Emergent macroscopic manifestations
of these molecular interactions, such as the length-force relationship and its
associated length adaptation, are well documented, but the molecular constituents
and organization that give rise to these emergent muscle behaviors remain largely
unknown. In this minireview, we describe emergent properties of airway smooth
muscle that seem to have originated from inherent fragility of the cellular structures, which has been increasingly recognized as a unique and important smooth
muscle attribute. We also describe molecular interactions (based on direct and
indirect evidence) that may confer malleability on fragile structural elements that in
turn may allow the muscle to adapt to large and frequent changes in cell dimensions. Understanding how smooth muscle works may hinge on how well we can
relate molecular events to its emergent macroscopic functions.
Review
EMERGENT PROPERTIES OF AIRWAY SMOOTH MUSCLE
Fig. 1. A: length-force relationship of smooth muscle. Gray lines depict the same
relationship in striated muscle, redrawn from Gordon et al. (14) as a reference, with
permission from John Wiley and Sons, Ltd. Solid lines are linear fits of data from
airway smooth muscle (ASM) adapted to different lengths. The red arrows with
dotted lines depict sequences and directions of changes in force after shortening
from the reference length and after stretch from the reference length during the
process of length adaptation. See text for more detail. B: schematic of a smooth
muscle contractile unit. Dotted arrows indicate the direction of movement of thin
filaments (and their associated dense bodies) during active shortening.
ferent in smooth muscle. This difference can be dissected into
at least two aspects; the first is that the shapes of the lengthforce curves (at least the ascending portion of the curves) are
different, and the second is that in smooth muscle the lengthforce relationship cannot be represented by any single curve.
Mechanisms underlying these differences are likely different
and are discussed separately as follows.
The shape of the length-force curve in smooth muscle should
reflect the structural constraint imposed by the contractile unit,
similar to the situation in striated muscle. Based on the observed linear relationship of the individual length-force curves
shown in Fig. 1A, a simple model can be constructed that
predicts such a relationship (Fig. 1B) if two assumptions are
made. 1) In a fully adapted smooth muscle (to any particular
length), the myosin (thick) filament overlaps the actin (thin)
filaments completely and spans the whole distance from dense
body to dense body. 2) Once slid over the dense bodies the
ends of the myosin filament no longer contribute to force
generation. With these assumptions, the model predicts a linear
length-force relationship because the overlap between the thin
and thick filaments decreases linearly as the muscle length (or
the length of the contractile unit) decreases.
As shown in Fig. 1A, the linear length-force relationship of
smooth muscle can be shifted in a process called length
adaptation. As indicated by the red dotted arrows (Fig. 1A), if
the length of the muscle is suddenly shortened, for example,
J Appl Physiol • VOL
from an arbitrarily chosen reference length (Lref) (at which the
muscle has been fully adapted) by 25%, the force will decrease
in proportion to the amount of length change; if the muscle is
allowed to “recover” (usually over a period of 30 min during
which the muscle is briefly stimulated at 5-min intervals) at the
shortened length, the force returns to the maximal value before
the length change (18, 38), and in the process shifts the whole
length-force curve to the left. This is commonly referred to as
length adaptation (1). Length adaptation works in both directions, that is, if the muscle is stretched (and full force recovery
is allowed to occur), the length-force relationship will shift to
the right (Fig. 1A).
Several lines of evidence suggest that length adaptation
accompanies structural changes that alter the number of contractile units, especially the units in series spanning the cell
length (38, 46, 25). Maximization of the overlap between the
thick and thin filaments at different cell length is speculated to
be the result of structural remodeling, as supported by the
evidence of recovery of maximal force at different adapted
lengths. The model also explains the increase in velocity and
power output when the muscle is adapted at a longer length
while preserving length independence of maximal active force
(18, 25, 38).
Force-fluctuation induced relengthening. The extent of
ASM shortening in vivo is not determined by the length-force
relationship described above, but by a complex interaction
among several variables. Many of these variables come into
play because the muscle resides in a mechanical environment
that is dynamic: the muscle is constantly subjected to periodic
stretches due to fluctuations in the transmural pressures in the
airways because of the action of breathing. Applying force
fluctuations of physiological amplitude and timing to contracted ASM causes the contracted muscle to relengthen substantially (9 –10, 13, 29). The amount of relengthening can be
altered by intervention of specific signaling pathways governing muscle activation. Inhibition of p38 MAPK and the upstream activator of ERK1/2 (i.e., MEK) potentiates relengthening of maximally activated ASM (8, 28); this potentiation
appears to be mediated by regulation of phosphorylation of the
27-kDa heat shock protein (HSP27) (27) and h-caldesmon, a
protein known to cross-link the thin and thick filaments (8). It
is not clear how phosphorylation of HSP27 and h-caldesmon is
linked to force-fluctuation-induced relengthening, but it is
speculated that the phosphorylation may affect the thin filament length, leading to shorter contractile unit length and
reduced actin-myosin-actin connectivity within the contractile
units, which in turn translates into a reduced overlap between
the contractile filaments during the length oscillation (caused
by the force fluctuation) (30).
In force-fluctuation-induced ASM relengthening, some degree of plastic deformation can be observed. In going from
small- to large-amplitude oscillation, the amount of relengthening increases; however, when returning from a large-amplitude oscillation to oscillation at a smaller amplitude, the
amount of relengthening is not accordingly reduced, but remains at about the same level as that observed during the
large-amplitude oscillation (13, 28). It appears that length
adaptation and structural malleability may play a role in this
nonreversibility.
Cytoskeletal reinforcement. In response to the application of
a localized physical force, as by an attached microbead, there
110 • APRIL 2011 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.32.247 on June 17, 2017
Dense body
1131
Review
1132
EMERGENT PROPERTIES OF AIRWAY SMOOTH MUSCLE
(40, 48, 49). For oscillatory cell stretching, strain-rate amplitude is proportional to the product of the length change and the
frequency; for a muscle of unit length, the strain-rate amplitude
corresponds to the peak velocity in the oscillatory cycle. When
viewed as a function of the strain-rate amplitude alone, length
adaptation, on the one hand, and actomyosin bridge dynamics,
on the other, can be unified (34). To explain this unification,
Oliver et al. (34) pictured molecular rearrangements within the
cytoskeleton as being governed by long-lived microconfigurations in which stress-bearing molecules become trapped. For
small strain rates, the relaxation time must remain close to its
natural (slow) time scale, whereas for larger strain rates another time scale enters into the problem, namely, the strain rate
itself (66).
CHANGES IN CELLULAR CONSTITUENTS AND THEIR
ORGANIZATION DUE TO MECHANICAL PERTURBATION
A common requirement for the emergence of the abovedescribed smooth muscle behaviors is structural malleability of
the cell. This property probably originates from multiple levels
of the structural organization of the muscle cell that include
weak interactions among the structural elements of the cytoskeleton and between actin and myosin within the confine of
the contractile unit, linkages between structural elements that
are readily modifiable, and lability of the structural elements
themselves. Some of these structural remodelings may be
mediated by chemical signaling triggered by mechanosensors
on the cell membrane; others may be a direct result of mechanical perturbation.
Evanescence of myosin and actin filaments. The lengths of
thick and thin filaments in striated muscle are fixed, and they
do not change under physiological conditions (50). In smooth
muscle, there is no consensus regarding the lengths of the thick
Fig. 2. Cell mapping rheometry of human airway smooth
muscle cell. A: traction map before cell stretch. B: traction
map immediately after an imposed homogeneous biaxial
stretch of a 4-s stretch-unstretch maneuver with a peak
strain amplitude of 10%. The cell tractions are markedly
ablated. C: traction map at 1,000 s following stress cessation. Tractions have largely recovered to the prestretch
value. D: traction field can be used to compute the contractile moment, T, corresponding to an equivalent force
dipole. At the earliest measurable time point following
stretch (b), the contractile moment was significantly reduced to 20% of its baseline value (a) followed by a slow
recovery (c). Reproduced from Ref. 23 under its Creative
Commons Attribution License.
J Appl Physiol • VOL
110 • APRIL 2011 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.32.247 on June 17, 2017
occurs rapid actin polymerization and increased focal adhesion
assembly, resulting in increases in cytoskeletal stiffness and
traction forces (41, 61– 62). This phenomenon is called cytoskeletal reinforcement. But if left unopposed, reinforcement
would progressively impede cell stretch, and organ stretch, and
thus could become a self-defeating strategy of cytoskeletal
mechanoprotection. To maintain a homeostatic balance, an
opposing phenomenon is required. Indeed, fluidization is now
seen as being reinforcement’s opposite (5, 23, 57). In response
to a uniform biaxial or uniaxial cell stretch, the cytoskeleton
exhibits a prompt decrease of stiffness and increase in macromolecular mobility (23, 57); an example is shown in Fig. 2. In
response to stretch, therefore, the cell might either reinforce, a
bracing-type of physiological response, or fluidize, a stressrelieving physiological response.
Cytoskeletal fluidization and resolidification. The fluidization response is prompt and is mediated by the effects of
physical forces acting directly on a material, the cytoskeleton,
that is innately fragile (3–5, 7, 11, 12, 23, 31, 51, 57, 58, 71).
It remains unclear, however, what the underlying mechanism
might be. Perturbed myosin binding is certainly a large contributor; physical forces can pull myosin heads away from actin
filaments, but other weak cross-linking bonds can be disrupted
as well (24, 44, 63, 65). Depolymerization of F-actin in
response to stretch has also been known for a long time (37),
but based on existing data, that depolymerization process was
thought to be too slow to account for prompt cytoskeletal
fluidization. Recent data, however, have implicated stretchinduced actin depolymerization (5); evanescence of actin filaments is described in greater detail below.
Strain-rate invariance. To the extent that the ASM cell is
seen as being a highly malleable material, it shares many
features with soft inert materials such as foams, clays, pastes,
colloids, and emulsions, all of which, like ASM, show relaxation dynamics that are not tied to any internal scale of time
Review
EMERGENT PROPERTIES OF AIRWAY SMOOTH MUSCLE
J Appl Physiol • VOL
stretched length. However, they do not behave like ordinary
cables when the muscle cell is shortened. These cables do not
buckle but instead are able to adjust their length (within
seconds) and remain more or less straight even when the cell
length is reduced by half (68). It appears that the DB cables are
plastic structures able to alter their lengths according to cell
length. This property may be responsible for the constant
stiffness in the relaxed ASM observed in a wide range of
adapted cell lengths (2, 68).
Vimentin is one of the major proteins that make up intermediate filaments. Regulation of the length of DB cables is
likely linked to regulation of the length of the intermediate
filaments. It has been shown that phosphorylation of vimentin
occurs during smooth muscle activation and that phosphorylation of vimentin leads to disassembly of intermediate filaments
(32, 53, 64). This may be the molecular mechanism by which
the length of DB cables is regulated. That is, intermediate
filaments disassemble on activation, and when the muscle
settles to its final resting length after relaxation and dephosphorylation of vimentin, reassembly of intermediate filaments
at a different length occurs.
Dynamics in thin filament attachment to dense plaques. In
skeletal muscle, a single cell spans from tendon to tendon, and
the cell-tendon connection is a permanent structure in that its
structural organization does not change with the contractionrelaxation cycle. In cardiac muscle, individual myocytes are
connected to one another through intercalated discs which are
also permanent structures. In smooth muscle, there is evidence
that the dense plaques that couple adjacent cells mechanically
may not be permanent structures (15). It has been demonstrated
in ASM that recruitment of structural and signaling proteins to
the cell cortex is associated with muscle stimulation, and that
this recruitment stimulates association of adhesion proteins to
␤-integrins (22, 36, 67, 69 –70) presumably at the sites of dense
plaques. Some of the important events that occur at the adhesion sites during activation are polymerization of actin filaments and attachment of the filaments to anchoring proteins,
which also provide linkages to integrins and the extracellular
matrix.
While the permanent mechanical connection adopted by
striated muscle may be energetically more efficient, it does not
provide malleability required by smooth muscle. For length
adaptation to occur, complex mechanisms regulating denseplaque function must be in place to ensure that the cytoskeleton
and the mechanical couplings are rigid enough for force generated by the muscle to be transmitted to the outside world, and
yet flexible enough that the structures can be modified to
accommodate large change in cell geometry.
UNDERSTANDING SMOOTH MUSCLE FUNCTION IN
RELATION TO STRUCTURAL MALLEABILITY
It is obvious that many of the emergent smooth muscle
properties stem from structural malleability of the cell. How
structural properties determine functionality in smooth muscle
is, for the most part, still an unanswered question. To apply the
systems biology approach in understanding smooth muscle
function, we need to integrate data at all levels, from proteinprotein interaction to the manifested mechanical properties.
Recent development in smooth muscle research, especially in
ASM research, has switched our focus on regulation of acto-
110 • APRIL 2011 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.32.247 on June 17, 2017
and thin filaments; there is strong evidence suggesting that the
filament lengths are not constant (45).
Myosin monomers of smooth muscle are able to self-assemble into filaments. It has been shown that the filaments are not
stable when the regulatory light chain of the myosin is not
phosphorylated, while filaments of myosin with the light chain
phosphorylated are much more stable (42, 52). It is further
shown that a conformational change in the phosphorylated vs.
nonphosphorylated myosin is likely responsible for the filament stability (6, 35, 47, 59, 60). Direct test of the physical
integrity of ASM myosin filaments confirms that phosphorylated myosin monomers are able to form filaments that are
much more resistant to ultrasonic agitation in solution (20).
The above cited studies were all carried out in solution. In
intact ASM cells it has been shown later that the light chain
phosphorylation also regulates thick filament lability (39).
Lability of thick filaments in intact ASM can be demonstrated in at least two ways. An increase in thick filament mass
has been shown to be associated with muscle activation (16,
17, 25); mechanical agitation in the form of length oscillation
applied to relaxed ASM has also been shown to transiently
reduce the thick filament mass (26). The change in filament
mass is completely reversible if the muscle is allowed to
recover under static conditions. Interestingly, change in isometric force due to length oscillation parallels that of thick
filament mass (26). These findings suggest that thick filaments
disassemble in response to externally applied strain and reassemble in the absence of mechanical disturbance. The evanescence of thick filaments is likely one of the important intrinsic
properties of ASM that gives rise to the phenomenon of length
adaptation (25).
The thin filaments in smooth muscle, like the thick filaments,
are not static structures resistant to remodeling. Actin polymerization has been shown to occur with activation of ASM (17,
19, 21, 33, 56), and the polymerization is critical for normal
force development (33). Polymerization of actin filaments in
ASM is extensively regulated; increasing details of the signaling pathway are being revealed mainly due to the work being
done in the Gunst laboratory (15). It appears that regulation of
actin dynamics in smooth muscle shares some similarity with
that in migrating cells. It has been demonstrated that the actin
nucleation promoting factor, N-WASp, is involved in the
activation of the actin nucleation protein, Arp2/3, that in turn
leads to actin polymerization (69). When the intracellular
process of actin polymerization is disrupted, tension development in the muscle in response to stimulation is invariably
attenuated (54, 55, 69, 70). Involvement of integrin-linked
kinase in actin polymerization (70) suggests that mechanical
stress or strain could be an important trigger for actin network
remodeling.
Plasticity of the dense-body structure. Another structural
element in ASM that exhibits malleability is the dense body
(DB) cable, a longitudinal aggregate of dense bodies flanked
by intermediate filaments. It has been found in ASM that there
are numerous DB cables that run in parallel with the contractile
filaments within any cell segment (68). These cables appear to
be able to support passive tension (in the relaxed muscle)
because stretching the muscle cells straightens the cables (68).
The DB cables behave like ordinary cables, able to support
tensile stress when the muscle cell is suddenly stretched, and
undergo “stress relaxation” when the cell is maintained at the
1133
Review
1134
EMERGENT PROPERTIES OF AIRWAY SMOOTH MUSCLE
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
GRANTS
This work was supported by the Canadian Institutes of Health Research
(MOP-13271, MOP-37924) and the National Institutes of Health (HL084224).
19.
20.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
21.
REFERENCES
1. Bai TR, Bates JH, Brusasco V, Camoretti-Mercado B, Chitano P,
Deng LH, Dowell M, Fabry B, Ford LE, Fredberg JJ, Gerthoffer WT,
Gilbert SH, Gunst SJ, Hai CM, Halayko AJ, Hirst SJ, James AL,
Janssen LJ, Jones KA, King GG, Lakser OJ, Lambert RK, Lauzon
AM, Lutchen KR, Maksym GN, Meiss RA, Mijailovich SM, Mitchell
HW, Mitchell RW, Mitzner W, Murphy TM, Paré PD, Schellenberg
RR, Seow CY, Sieck GC, Smith PG, Smolensky AV, Solway J,
Stephens NL, Stewart AG, Tang DD, Wang L. On the terminology for
describing the length-force relationship and its changes in airway smooth
muscle. J Appl Physiol 97: 2029 –2034, 2004.
2. Bossé Y, Solomon D, Chin LY, Lian K, Paré PD, Seow CY. Increase in
passive stiffness at reduced airway smooth muscle length: potential impact
J Appl Physiol • VOL
22.
23.
24.
on airway responsiveness. Am J Physiol Lung Cell Mol Physiol 298:
L277–L287, 2010.
Bursac P, Fabry B, Trepat X, Lenormand G, Butler JP, Wang N,
Fredberg JJ, An SS. Cytoskeleton dynamics: fluctuations within the
network. Biochem Biophys Res Commun 355: 324 –330, 2007.
Bursac P, Lenormand G, Fabry B, Oliver M, Weitz DA, Viasnoff V,
Butler JP, Fredberg JJ. Cytoskeletal remodelling and slow dynamics in
the living cell. Nat Mater 4: 557–561, 2005.
Chen C, Krishnan R, Zhou E, Ramachandran A, Tambe D, Rajendran K, Adam RM, Deng L, Fredberg JJ. Fluidization and resolidification of the human bladder smooth muscle cell in response to transient
stretch. PLoS One 5(8). pii: e12035, 2010.
Craig R, Smith R, Kendrick-Jones J. Light-chain phosphorylation
controls the conformation of vertebrate non-muscle and smooth muscle
myosin molecules. Nature 302: 436 –439, 1983.
Deng L, Trepat X, Butler JP, Millet E, Morgan KG, Weitz DA,
Fredberg JJ. Fast and slow dynamics of the cytoskeleton. Nat Mater 5:
636 –640, 2006.
Dowell ML, Lavoie TL, Lakser OJ, Dulin NO, Fredberg JJ, Gerthoffer WT, Seow CY, Mitchell RW, Solway J. MEK modulates force
fluctuation-induced relengthening of canine tracheal smooth muscle. Eur
Respir J 36: 630 –637, 2010.
Fabry B, Fredberg JJ. Remodeling of the airway smooth muscle cell: are
we built of glass? Respir Physiol Neurobiol 137: 109 –124, 2003.
Fabry B, Fredberg JJ. Mechanotransduction, asthma, and airway smooth
muscle. Drug Discov Today Dis Models 4: 131–137, 2007.
Fabry B, Maksym GN, Butler JP, Glogauer M, Navajas D, Fredberg
JJ. Scaling the microrheology of living cells. Phys Rev Lett 87: 148102,
2001.
Fabry B, Maksym GN, Butler JP, Glogauer M, Navajas D, Taback
NA, Millet EJ, Fredberg JJ. Time scale and other invariants of integrative mechanical behavior in living cells. Phys Rev E Stat Nonlin Soft
Matter Phys 68: 041914, 2003.
Fredberg JJ, Inouye DS, Mijailovich SM, Butler JP. Perturbed equilibrium of myosin binding in airway smooth muscle and its implications in
bronchospasm. Am J Respir Crit Care Med 159: 959 –967, 1999.
Gordon AM, Huxley AF, Julian FJ. The variation in isometric tension
with sarcomere length in vertebrate muscle fibres. J Physiol 184: 170 –
192, 1966.
Gunst SJ, Zhang W. Actin cytoskeletal dynamics in smooth muscle: a
new paradigm for the regulation of smooth muscle contraction. Am J
Physiol Cell Physiol 295: C576 –C587, 2008.
Herrera AM, Kuo KH, Seow CY. Influence of calcium on myosin thick
filament formation in intact airway smooth muscle. Am J Physiol Cell
Physiol 282: C310 –C316, 2002.
Herrera AM, Martinez EC, Seow CY. Electron microscopic study of
actin polymerization in airway smooth muscle. Am J Physiol Lung Cell
Mol Physiol 286: L1161–L1168, 2004.
Herrera AM, McParland BE, Bienkowska A, Tait R, Paré PD, Seow
CY. ‘Sarcomeres’ of smooth muscle: functional characteristics and ultrastructural evidence. J Cell Sci 118: 2381–2392, 2005.
Hirshman CA, Togashi H, Shao D, Emala CW. Galphai-2 is required
for carbachol-induced stress fiber formation in human airway smooth
muscle cells. Am J Physiol Lung Cell Mol Physiol 275: L911–L916, 1998.
Ip K, Sobieszek A, Solomon D, Jiao Y, Paré PD, Seow CY. Physical
integrity of smooth muscle myosin filaments is enhanced by phosphorylation of the regulatory myosin light chain. Cell Physiol Biochem 20:
649 –658, 2007.
Jones KA, Perkins WJ, Lorenz RR, Prakash YS, Sieck GC, Warner
DO. F-actin stabilization increases tension cost during contraction of
permeabilized airway smooth muscle in dogs. J Physiol 519: 527–538,
1999.
Kim HR, Hoque M, Hai CM. Cholinergic receptor-mediated differential
cytoskeletal recruitment of actin- and integrin-binding proteins in intact
airway smooth muscle. Am J Physiol Cell Physiol 287: C1375–C1383,
2004.
Krishnan R, Park CY, Lin YC, Mead J, Jaspers RT, Trepat X,
Lenormand G, Tambe D, Smolensky AV, Knoll AH, Butler JP,
Fredberg JJ. Reinforcement versus fluidization in cytoskeletal mechanoresponsiveness. PLoS One 4: e5486, 2009.
Kroy K, Glaser J. “The Glassy Wormlike Chain.” New J Physics 9: 416,
2007.
110 • APRIL 2011 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.32.247 on June 17, 2017
myosin interaction to a broader focus that includes regulation
of structural changes within the muscle cells during contraction
and relaxation. Given that structural alterations in cytoskeleton
and contractile apparatus can affect smooth muscle force and
stiffness development (2, 26, 33, 38, 46, 67, 68 –70), velocity
of shortening, (25, 38, 46) power output (25), and relengthening during contraction (8, 13, 27–28), we can no longer
interpret mechanical data from smooth muscle solely based on
models of actomyosin interaction.
Smooth muscle shares with nonmuscle motile cells many
features in terms of their activation pathways. One can speculate that the reason behind this is the common need for
flexibility in the subcellular structures. In order to maintain
structural malleability, smooth muscle appears to have taken a
separate path in evolution from that taken by striated muscle.
The latter appears to have streamlined the activation pathway
for efficiency, because it does not need structural malleability
in order to operate over a large length range. This insight is
probably useful in guiding our research approach and puts less
emphasis on the similarities between smooth and striated muscles,
and more on the similarities between smooth muscle and motile
nonmuscle cells. The rich literature dealing with regulation of
motility in nonmuscle cells has been, and will likely continue to
be, very relevant to smooth muscle research (15).
Although progress has been made, there are still many
challenges in our attempt to understand emergent smooth
muscle function based on specific molecular interactions and
structural modifications. A major one is the lack of sufficient
ultrastructural data, specifically those dealing with changes at
the ultrastructural level due to mechanical or chemical interventions. Therefore there are still many gaps in the links
between specific molecular mechanisms and the emergent
behaviors. There is also a lack of sufficient information regarding the interactions among the various molecular processes that
lead to structural modification and the emergent properties.
Nevertheless, by overcoming these challenges we will be
rewarded with opportunities to identify drug targets that can
change the outcome of molecular interactions, thus providing
guidance for therapeutic approaches in treating many smooth
muscle-related diseases.
Review
EMERGENT PROPERTIES OF AIRWAY SMOOTH MUSCLE
J Appl Physiol • VOL
48. Sollich P. Rheological constitutive equation for a model of soft glassy
materials. Phys Rev E 58: 738 –759, 1998.
49. Sollich P, Lequeux F, Hebraud P, Cates ME. Rheology of soft glassy
materials. Phys Rev Lett 78: 2020 –2023, 1997.
50. Sosa H, Popp D, Ouyang G, Huxley HE. Ultrastructure of skeletal
muscle fibers studied by a plunge quick freezing method: myofilament
lengths. Biophys J 67: 283–292, 1994.
51. Sunyer R, Trepat X, Fredberg JJ, Farré R, Navajas D. The temperature dependence of cell mechanics measured by atomic force microscopy.
Phys Biol 6: 025009, 2009.
52. Suzuki H, Onishi H, Takahashi K, Watanabe S. Structure and function
of chicken gizzard myosin. J Biochem (Tokyo) 84: 1529 –1542, 1978.
53. Tang DD, Bai Y, Gunst SJ. Silencing of p21-activated kinase attenuates
vimentin phosphorylation on Ser-56 and reorientation of the vimentin
network during stimulation of smooth muscle cells by 5-hydroxytryptamine. Biochem J 388: 773–783, 2005.
54. Tang DD, Gunst SJ. The small GTPase Cdc42 regulates actin polymerization and tension development during contractile stimulation of smooth
muscle. J Biol Chem 279: 51722–51728, 2004.
55. Tang DD, Zhang W, Gunst SJ. The adapter protein CrkII regulates
neuronal Wiskott-Aldrich syndrome protein, actin polymerization, and
tension development during contractile stimulation of smooth muscle. J
Biol Chem 280: 23380 –23389, 2005.
56. Togashi H, Emala CW, Hall IP, Hirshman CA. Carbachol-induced
actin reorganization involves Gi activation of Rho in human airway
smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 274: L803–
L809, 1998.
57. Trepat X, Deng L, An SS, Navajas D, Tschumperlin DJ, Gerthoffer
WT, Butler JP, Fredberg JJ. Universal physical responses to stretch in
the living cell. Nature 447: 592–595, 2007.
58. Trepat X, Lenormand G, Fredberg JJ. Universality in cell mechanics.
Soft Matter 4: 1750 –1759, 2008.
59. Trybus KM, Huiatt TW, Lowey S. A bent monomeric conformation of
myosin from smooth muscle. Proc Natl Acad Sci USA 79: 6151–6155,
1982.
60. Trybus KM, Lowey S. Conformational states of smooth muscle myosin.
Effects of light chain phosphorylation and ionic strength. J Biol Chem 259:
8564 –8571, 1984.
61. von Wichert G, Jiang G, Kostic A, De Vos K, Sap J, Sheetz MP.
RPTP-alpha acts as a transducer of mechanical force on alphav/beta3integrin-cytoskeleton linkages. J Cell Biol 161: 143–153, 2003.
62. von Wichert G, Haimovich B, Feng GS, Sheetz MP. Force-dependent
integrin-cytoskeleton linkage formation requires downregulation of focal
complex dynamics by Shp2. EMBO J 22: 5023–5035, 2003.
63. Wang I, Politi AZ, Tania N, Bai Y, Sanderson MJ, Sneyd J. A
mathematical model of airway and pulmonary arteriole smooth muscle.
Biophys J 94: 2053–2064, 2008.
64. Wang R, Li Q, Tang DD. Role of vimentin in smooth muscle force
development. Am J Physiol Cell Physiol 291: C483–C489, 2006.
65. Wolff L, Fernandez P, Kroy K. Inelastic mechanics of sticky biopolymer
networks. New J Physics 12: 053024, 2010.
66. Wyss HM, Miyazaki K, Mattsson J, Hu Z, Reichman DR, Weitz DA.
Strain-rate frequency superposition: a rheological probe of structural
relaxation in soft materials. Phys Rev Lett 98: 238303, 2007.
67. Zhang W, Gunst SJ. Dynamic association between alpha-actinin and
beta-integrin regulates contraction of canine tracheal smooth muscle. J
Physiol 572: 659 –676, 2006.
68. Zhang J, Herrera AM, Pare PD, Seow CY. Dense-body aggregates as
plastic structures supporting tension in smooth muscle cells. Am J Physiol
Lung Cell Mol Physiol 299: L631–L638, 2010.
69. Zhang W, Wu Y, Du L, Tang DD, Gunst SJ. Activation of the Arp2/3
complex by N-WASp is required for actin polymerization and contraction
in smooth muscle. Am J Physiol Cell Physiol 288: C1145–C1160, 2005.
70. Zhang W, Wu Y, Wu C, Gunst SJ. Integrin-linked kinase regulates
N-WASp-mediated actin polymerization and tension development in tracheal smooth muscle. J Biol Chem 282: 34568 –34580, 2007.
71. Zhou EH, Trepat X, Park CY, Lenormand G, Oliver MN, Mijailovich
SM, Hardin C, Weitz DA, Butler JP, Fredberg JJ. Universal behavior
of the osmotically compressed cell and its analogy to the colloidal glass
transition. Proc Natl Acad Sci USA 106: 10632–10637, 2009.
110 • APRIL 2011 •
www.jap.org
Downloaded from http://jap.physiology.org/ by 10.220.32.247 on June 17, 2017
25. Kuo KH, Herrera AM, Wang L, Paré PD, Ford LE, Stephens NL,
Seow CY. Structure-function correlation in airway smooth muscle adapted
to different lengths. Am J Physiol Cell Physiol 285: C384 –C390, 2003.
26. Kuo KH, Wang L, Pare PD, Ford LE, Seow CY. Myosin thick filament
lability induced by mechanical strain in airway smooth muscle. J Appl
Physiol 90: 1811–1816, 2001.
27. Lakser OJ, Dowell ML, Hoyte FL, Chen B, Lavoie TL, Ferreira C,
Pinto LH, Dulin NO, Kogut P, Churchill J, Mitchell RW, Solway J.
Steroids augment relengthening of contracted airway smooth muscle:
potential additional mechanism of benefit in asthma. Eur Respir J 32:
1224 –1230, 2008.
28. Lakser OJ, Lindeman RP, Fredberg JJ. Inhibition of the p38 MAP
kinase pathway destabilizes smooth muscle length during physiological
loading. Am J Physiol Lung Cell Mol Physiol 282: L1117–L1121, 2002.
29. Latourelle J, Fabry B, Fredberg JJ. Dynamic equilibration of airway
smooth muscle contraction during physiological loading. J Appl Physiol
92: 771–779, 2002.
30. Lavoie TL, Dowell ML, Lakser OJ, Gerthoffer WT, Fredberg JJ,
Seow CY, Mitchell RW, Solway J. Disrupting actin-myosin-actin connectivity in airway smooth muscle as a treatment for asthma? Proc Am
Thorac Soc 6: 295–300, 2009.
31. Lenormand G, Chopin J, Bursac P, Fredberg JJ, Butler JP. Directional memory and caged dynamics in cytoskeletal remodelling. Biochem
Biophys Res Commun 360: 797–801, 2007.
32. Li QF, Spinelli AM, Wang R, Anfinogenova Y, Singer HA, Tang DD.
Critical role of vimentin phosphorylation at Ser-56 by p21-activated
kinase in vimentin cytoskeleton signaling. J Biol Chem 281: 34716 –
34724, 2006.
33. Mehta D, Gunst SJ. Actin polymerization stimulated by contractile
activation regulates force development in canine tracheal smooth muscle.
J Physiol 519: 829 –840, 1999.
34. Oliver M, Kováts T, Mijailovich SM, Butler JP, Fredberg JJ, Lenormand G. Remodeling of integrated contractile tissues and its dependence
on strain-rate amplitude. Phys Rev Lett 105: 158102, 2010.
35. Onishi H, Wakabayashi T. Electron microscopic studies of myosin
molecules from chicken gizzard muscle I: the formation of the intramolecular loop in the myosin tail. J Biochem (Tokyo) 92: 871–879, 1982.
36. Opazo Saez A, Zhang W, Wu Y, Turner CE, Tang DD, Gunst SJ.
Tension development during contractile stimulation of smooth muscle
requires recruitment of paxillin and vinculin to the membrane. Am J
Physiol Cell Physiol 286: C433–C447, 2004.
37. Pender N, McCulloch CA. Quantitation of actin polymerization in two
human fibroblast sub-types responding to mechanical stretching. J Cell Sci
100: 187–193, 1991.
38. Pratusevich VR, Seow CY, Ford LE. Plasticity in canine airway smooth
muscle. J Gen Physiol 105: 73–94, 1995.
39. Qi D, Mitchell RW, Burdyga T, Ford LE, Kuo KH, Seow CY. Myosin
light chain phosphorylation facilitates in vivo myosin filament reassembly
after mechanical perturbation. Am J Physiol Cell Physiol 282: C1298 –
C1305, 2002.
40. Ritort F, Sollich P. Glassy dynamics of kinetically constrained models.
Adv Physics 52: 219 –342, 2003.
41. Sawada Y, Tamada M, Dubin-Thaler BJ, Cherniavskaya O, Sakai R,
Tanaka S, Sheetz MP. Force sensing by mechanical extension of the Src
family kinase substrate p130Cas. Cell 127: 1015–1026, 2006.
42. Scholey JM, Taylor KA, Kendrick-Jones J. Regulation of non-muscle
myosin assembly by calmodulin-dependent light chain kinase. Nature 287:
233–235, 1980.
43. Schrödinger E. What Is Life? Cambridge, UK: Cambridge Univ. Press, 1944.
44. Semmrich C, Storz T, Glaser J, Merkel R, Bausch AR, Kroy K. Glass
transition and rheological redundancy in F-actin solutions. Proc Natl Acad
Sci USA 104: 20199 –20203, 2007.
45. Seow CY. Myosin filament assembly in an ever-changing myofilament
lattice of smooth muscle. Am J Physiol Cell Physiol 289: C1363–C1368,
2005.
46. Seow CY, Pratusevich VR, Ford LE. Series-to-parallel transition in the
filament lattice of airway smooth muscle. J Appl Physiol 89: 869 –876,
2000.
47. Smith RC, Cande WZ, Craig R, Tooth PJ, Scholey JM, KendrickJones J. Regulation of myosin filament assembly by light-chain phosphorylation. Philos Trans R Soc Lond B Biol Sci 302: 73–82, 1983.
1135