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Mechanical Signal Transduction: DivergentCommunication and the PotentialConsequences for Masticatory MuscleElisabeth R. Barton

Skeletal muscle can readily respond to physiological demands, causing

changes in muscle mass and the fiber properties to meet the functional

needs. Muscle adaptation is a coordination of endocrine, metabolic, and

mechanical signals resulting in changes at the transcriptional and transla-

tional levels. New evidence suggests that the signal transduction pathways

that are responsive to mechanical changes diverge in the craniofacial and

axial muscles. Two regions where sensors for load exist, the sarcolemma

and the contractile apparatus, have many proteins that are poised to convert

mechanical perturbations into molecular signals and ultimately into

changes in gene expression. Changes in the mechanical signal transduction

system might contribute to unique physiological and pathologic features of

masticatory muscle. This review will define the molecular components that

form a new set of intrinsic factors that could lead to myogenic temporo-

mandibular joint disorders. (Semin Orthod 2012;18:2-9.) © 2012 Published by

Elsevier Inc.

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S keletal muscle has the remarkable ability toadapt to changes in workload. Almost all

uscle properties can be modulated, such asuscle fiber size, contractile properties, and me-

abolism. Changes in patterns of gene expres-ion as well as shifts in the balance betweenrotein synthesis and degradation are required

o complete the adaptational response. Coordi-ation of mechanical, chemical, and metabolic

nformation regarding how well the existingroperties meet the demands on the tissue helps

o instigate the process of muscle adaptation,nd this feedback helps to appropriately tuneuscle properties. Identification of major path-ays that directly regulate gene expression and

Department of Anatomy and Cell Biology, School of DentalMedicine and Pennsylvania Muscle Institute, University of Penn-sylvania, Philadelphia, PA.

Address correspondence to Elisabeth R. Barton, PhD, Depart-ment of Anatomy and Cell Biology, 441A Levy Bldg, 240 S. 40thStreet, University of Pennsylvania, Philadelphia, PA 19104.E-mail: erbarton@dental.upenn.edu

© 2012 Published by Elsevier Inc.1073-8746/12/1801-0$30.00/0

doi:10.1053/j.sodo.2011.09.002

2 Seminars in Orthodontics, Vol 18,

rotein synthesis/degradation demonstrateshat multiple inputs can converge on final com-

on pathways for muscle adaptation. However,orting out the contribution of the wide varietyf inputs on muscle adaptation has been moreifficult. Active force generation causes changesf multiple contributing signals in parallel, in-luding mechanical deformation, intracellularalcium flux, and depletion of high-energy sub-trates.

Recent research has begun to characterizehe initial sensors involved in relaying the me-hanical state of the muscle to the transcrip-ional and translational machinery. First, bothassive stretch and active contraction imposetress on proteins spanning the muscle plasmaembrane (sarcolemma) through physical asso-

iation with the cytoskeleton and the extracellu-ar matrix (ECM).1-4 Dynamic and tonic stressan be converted to molecular signals throughssociation with signaling cascades. In addition,here is now recognition that the contractilepparatus is not only the site for generatingorce but also a site for sensing force.5,6 Under-

standing the force-sensing proteins will help to

No 1 (March), 2012: pp 2-9

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3Mechanical Signal Transduction

elucidate the mechanisms underlying mechani-cal signal transduction and will provide new in-sight into variation between muscle groups, aswell as the basis for genetic diseases.

The contribution of mechanical signal trans-duction pathways to muscle adaptation is partic-ularly pertinent for masticatory muscle. Move-ment of the jaw for normal activity involvesshortening (concentric) and lengthening (ec-centric) contractions, and the latter drives load-sensing signals to a greater extent than otherpatterns of the force generation and is morelikely to cause injury.7 Furthermore, chronic

uscular activity such as bruxism might causextensive mechanical signaling leading to ana-olic drive in the masticatory muscle.8,9 This haseen proposed to underlie pain in the temporo-andibular region, even though the relation-

hip is controversial.10,11 However, the expectedonversion of pro-growth signals to muscle hy-ertrophy might not occur in the same manners that in other muscles in the body. Recentvidence from our laboratory suggests that mas-icatory muscles are tuned differently than axial

uscle in terms of sensing muscle activity andorce generation.12 Conversion of mechanical

information to muscle adaptation can occur interms of muscle growth and fiber properties, yetin the masticatory muscles, the shifts do not fallin line with the observations of limb muscles.Masticatory muscles respond to load differentlythan limb muscles, where the drive for anabolicprocesses is reduced and cell stress mediatedprocesses are enhanced. The goal of this reviewis to describe the distinctions of mechanicalsensing pathways between limb and head muscleand how the extrinsic force-generating patternsmight synergize with the intrinsic load-sensingproperties to result in myogenic pain and dys-function.

Signal Transduction PathwaysAssociated with the Sarcolemma

The regulation of muscle mass in response tochanges in load is driven through multiple sig-nal transduction pathways, which in turn leadsto shifts in the balance of protein synthesis anddegradation13,14 (Fig. 1). Systematic degrada-ion of muscle proteins occurs through muscle-pecific ubiquitin ligases (MaFbx/Atrogin-1 and

uscle RING finger 1 [MuRF1]), lysosomal pro-

eases (cathepsins) and caspases. Increased loadn skeletal muscles drives the anabolic arms ofhe pathways. These have been investigated inetail with models of muscle reloading, wherehe return of load causes transient increases inenes regulating cell cycle, cytoskeletal remod-ling, protein synthesis, inflammation, and pro-ection against apoptosis.15-18

Sensors for load are situated in the sarco-lemma, tethering the ECM to the intracellularactin cytoskeleton. In skeletal muscle, there are2 major complexes (Fig. 2). The focal adhesioncomplex is tethered by the �7/�1D integrin het-erodimer, which binds to the ECM, and talin,which binds to the actin cytoskeleton and thecytoplasmic tail of �1D integrin.19,20 The domi-nant connection in the second complex, thedystrophin glycoprotein complex (DGC), is viadystrophin, binding to the actin cytoskeletonand to the dystroglycan/sarcoglycan subcom-plexes, which in turn bind to laminin in theECM.21,22 The sarcoglycan (SG) complex is aubcomplex of the DGC that is composed of �-,

�-, �-, and �-SG in skeletal muscle.23,24 Theseproteins form an integral membrane complexwith a short intracellular domain, a single trans-membrane domain, and a large extracellulardomain. The intracellular regions of �-, �-, and�-SG have potential tyrosine phosphorylationsites. In cell culture studies, adhesion gives riseto phosphorylation of each of these SGs, indicat-ing that the SGs can be modified in response tocell attachment.25 Furthermore, we have beenable to isolate the SGs as players in the mechan-ical signal transduction process, where SG ty-rosine phosphorylation occurs after a series of

Figure 1. Pathways regulating muscle mass. Those ingreen in the online version are pro-growth pathways,whereas those in red in the online version result inloss of muscle mass. (Color version of figure is avail-able online.)

eccentric contractions in limb muscle, and dis-

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ruption of the SG complex in mice lacking �-SGeads to an aberrant extracellular signal-regu-ated kinase (ERK)1/2 response.26 On the basis

of these findings, the SG subcomplex has beenproposed to be a mechanosensor, which canmediate changes in load at the sarcolemma todistinct changes in gene expression and mainte-nance of muscle survival.

Both complexes are poised at the central siteof stress transmission and are important formaintaining membrane integrity.3 In addition totabilizing the membrane, the complexes canense mechanical stress and transmit that “out-ide-in” information back to the nucleus via sig-aling proteins associated with the complexes.either complex has inherent kinase or enzy-atic activity, but instead they rely on their as-

ociation with nonreceptor protein tyrosine ki-

Figure 2. Protein complexes in the sarcolemma invomuscle consists of dystrophin and filamin, intracellulmembrane proteins of the DGC; the dystroglycan comssociates with dystrophin on the intracellular domain

is in turn associated with the ECM (eg, laminin); anmembrane proteins that harbor potential tyrosine phoscomplex (�7 and �1D in skeletal muscle) spans the plasit is tethered to the cytoskeleton on the intracellular dcomplexes.20 (Adapted with permission from Barton ER

ases such as focal adhesion kinase (FAK) to

elay information from the ECM to the cell nu-leus.27-29 FAK activation affects its association

with other signaling proteins. These includeGrb2, an adapter protein associated with theRas-ERK/MAP kinase pathway, and p85, whichleads to activation of the phosphatidylinositol-3kinase (PI-3K)/Akt pathway. It is presumablythrough these interactions that FAK mediatessignaling30 and helps to maintain muscle massand cell survival.

In murine masticatory muscles, there are noapparent differences in the integrin or dystro-phin complex protein levels compared with limbmuscles, suggesting that the load-sensing capa-bility of masticatory muscles at the sarcolemma isnot impaired. However, mechanical signal trans-duction differs in masticatory muscle comparedwith limb muscle. By using the proportion of

in mechanical signal transduction. DGC in skeletaloteins attached to the cytoskeleton and the integralwhere the integral membrane protein �-dystroglycanwith �-dystroglycan in the extracellular space, which

e SG complex containing multiple single-pass integralylation sites in the intracellular domains. The integrinembrane where association with the ECM occurs, and

in by talin. FAK has been shown to interact with both(Color version of figure is available online.)

lvedar prplex,, andd thphorma moma

phosphorylated FAK that provides an index of

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5Mechanical Signal Transduction

loading/activity via these complexes,31 FAKphosphorylation showed higher activity in mas-seters compared with tibialis anterior or digas-tric muscles12 (Fig. 3). Thus, masseters areoaded to a greater extent than limb muscles orhe digastric muscles under normal conditionsithin the mouse. These results also demon-

trate that load sensing is intact in masseters,nd in normal animals, load by mastication (jawlosing in particular) might be more than loady ambulation.

Although this provides a snapshot of the steadytate in these muscles, it will be important to de-ermine whether the response of muscles of mas-ication to mechanical perturbation differs fromimb muscles, and how these differences modulate

uscle adaptation. Models of load-induced hyper-rophy and disuse atrophy have been developedrimarily in limb muscles (reviewed in Musac-hia32). For muscles of mastication, the least inva-

sive unloading model is to remove hard food andreplace it with soft food or a liquid diet, where

Figure 3. Phosphorylation of FAK (P-FAK) is elevatedin murine masseters (Mass) compared with limb mus-cle such as the tibialis anterior (TA) and also higherthan masticatory muscles involved with jaw openingsuch as the digastric muscle (Dig). Phosphorylation isnormalized to total FAK (T-FAK) for n � 3 muscles

er group. Statistical analysis is based on one-waynalysis of variance, followed by Tukey post hoc anal-sis. Results were described in part in a previous pub-

ication.12

without hard food, the muscles of mastication willundergo atrophy.33 An electromyogram (EMG)tudy of rats on liquid diet demonstrated that theaw-closing muscles (masseter, medial pterygoid,emporalis) had a drastic reduction in EMG activ-ty compared with mastication of hard food,hereas the jaw-opening muscles (eg, digastric)isplayed little change in activity.34 Dynamic load-

ng of masticatory muscles has relied on studies ofiomechanics and development of mastication invariety of species, including hamsters, rabbits,

nd pigs,35-37 which aid in understanding the nor-al and pathologic processes involved in humanastication. The larger species might be advanta-

eous in the study of masticatory movements be-ause of the overall geometrical similarity of theraniofacial skeleton and musculature to humans.owever, there is a distinct advantage to using

mall rodents for studies at the molecular levelecause of the availability of transgenic and geneargeted mice. Because all mammals possess theame developmental lineage for craniofacial mus-les, information gathered at the genomic androteomic levels can be translated across species.o this end, an in vivo mouse model of repetitivese has been described38 in which muscle injuryan be evaluated hours to days after the insult.

Signaling Pathways Associated With theContractile Apparatus

Additional load sensors are associated with thecontractile apparatus.5,39 The sarcomere is themallest functional unit in striated muscle and con-ains elements shown in Fig. 4. At the Z-line, sev-ral proteins are attached to provide structuralntegrity to the sarcomere. The primary compo-ent of the Z-line is �-actinin, which coordinates

he structural organization at the Z-line as well ashe intermolecular interactions among proteins.5

Other sarcomeric organizers include the giant pro-teins like titin, which spans the entire sarcomere,and nebulin, which runs the length of the thinfilament. In addition to a structural role, titinmight also play a role in mechanical signal trans-duction and might coordinate with several puta-tive signaling proteins that also associate with �-ac-tinin. Titin contains spring-like domains in itsI-band region in contrast to the very stiff domainsjuxtaposed to the Z-line. On muscle stretch, thesedomains can lengthen during muscle stretch and

provide retraction force to return the sarcomere to

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resting length, so there is a direct coupling be-tween force and titin structure.40 Associated withitin at the Z-line are proteins that also appear toense and integrate mechanical information, in-luding muscle LIM protein,41 telethonin, andyozenin.42 Of particular interest to the mastica-

ory muscles are the muscle ankyrin repeat pro-eins (MARPs), which are found in the I-bandegion.43-45 The skeletal muscle isoform Ankrd2as recently been proposed to be a dynamic stressensor. In response to mechanical stress on theuscle, there is increased Ankrd2 expression,43

but this protein also moves from its location withinthe sarcomeres to the nucleus after stretch andinjury, where it might regulate the expression ofadditional genes through interactions with p53.46,47

The M-band of the sarcomere also contains siteson titin that sense changes in muscle length.Titin possesses a kinase domain within the M-band, which might be activated by mechanicalforces.48 In addition to titin, other components

f the M-band have also been proposed as stress

Figure 4. Contractile apparatus proteins involved inof the contractile apparatus, spanning from Z-line tfilament, and the I-band is the region of the sarcomerportion of the sarcomere is the region of the thic(myozenin, telethonin, and muscle LIM protein are aso titin near the flexible spring-like region within theo the myosin thick filament and titin at the M-bandlignment. (Color version of figure is available online

ensors. Myomesin is a structural component of

he M-band that helps to cross-link the thicklaments. Rather than a rigid structure, myome-in provides elasticity, which might aid in buff-ring against contractile damage and tune thearcomere to changes in load.6

Both Ankrd2 and myomesin are expressed atlower levels in masticatory muscles versus limbmuscles.12 This suggests that mechanical signaltransduction in the cytoskeleton might be im-paired. Even though there is a heightened loadsignal originating at the sarcolemma, diminishedload signals from the contractile apparatus mightlead to miscommunication in the nucleus. Alter-natively, the mechanical message might result in adifferent type of adaptation in masticatory mus-cles.

Does Mechanical Signal TransductionDivergence Contribute to Fiber PropertyDistinctions?

Differential adaptation strategies might underlie

l transduction. The sarcomere is the functional unitine. The A-band spans the myosin-containing thickt lacks the thick filament. The M-band in the central

ament that lacks myosin heads. Signaling proteinsted with titin at the Z-line near �-actinin. MARPs bindd. Myomesin contains spring-like domains and bindsalso dimerizes with itself to maintain thick filament

signao Z-le thak filsociaI-banand

the morphologic and fiber property distinctions

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7Mechanical Signal Transduction

found in human masticatory muscles,49-51 fea-ures that have also been documented in manyther species, including mice, rabbits, andigs.52-54 One distinction is the increased propor-ion of hybrid fibers (those expressing multiple

yosin heavy chain [MHC] isoforms). It has beenroposed that the mixed composition allows forne-tuning of the rate and development of force.55

Second, human fibers have fetal and �-cardiacMHC in adult tissues, neither of which is present inlimb muscles.47 Fetal myosin is normally expressedduring development but can also indicate ongoingmuscle regeneration. Alpha-cardiac myosin ex-pression is normally restricted to the heart. Third,all muscle fibers appear smaller than their limbcounterparts. In addition, MHC I/� cardiac (slow)fiber cross-sectional area in masticatory muscles islarger than MHC IIA (fast oxidative) fibers in con-trast to MHC IIA fibers in the limb and trunk,which might contribute to lower power out-put.51,56 Finally, with age, most skeletal musclesexhibit a fast-to-slow shift in the fiber type distribu-tion. However, jaw muscles shift in the oppositedirection, where there is an increase in the fastfiber population.50 Simultaneous gene targeting ofall MARP family members leads to smaller musclefiber size and a fast-to-slow fiber type shift,57 sup-

orting that a reduction in MARP proteins couldead to small slow fibers in masticatory muscles, buthis has not been directly addressed.

Contributions of Mechanical SignalTransduction to Disorders ofMasticatory Muscle

The primary pathology associated with musclesof mastication is temporomandibular joint dis-order (TMD), which is characterized by chronicpain in this group of muscles and the temporo-mandibular joint. There is currently no unifiedtheory as to why TMD occurs, and why mostpatients are female.58,59 Because the myogeniclineage of masticatory muscles differs from axialmuscles, it is possible that factors that protectlimb muscles from prolonged pain or stress aremissing in jaw muscles, or that there is a differ-ent set point between the daily stress of muscleuse and the adaptations to that stress. A com-mon treatment strategy includes the reductionof load to the masticatory muscles, to which

many patients respond well. This suggests that a

large amount of TMD is caused by overload/overwork of the musculature and joint.

Differences in susceptibility and symptomscould be dependent on the development ofthese muscle groups or their physiological state.Alternatively, masticatory muscles might simplyadapt to the patterns of activity, as in otherexamples of muscle plasticity, resulting in a mus-cle with very different fiber properties than limbmuscles. Part of the adaptation might includemuscle turnover or compensatory hypertrophy,which would give rise to activated satellite cellsand expression of embryonic and neonatal my-osin. Indeed, the association of masseter hyper-trophy with TMD pathology has been pro-posed51 and could be part of a spectrum ofresponses within the masticatory muscles.

Ultimately, the emerging story is that theremight be a fundamentally different strategy formuscle design in the craniofacial muscles in gen-eral as compared with axial muscles. Whetherthis adaptation positions masticatory muscles ata set point that is ideal for their functions orwhether these strategies lead to heightened sus-ceptibilities to specific genetic or use-dependentpathologies has yet to be determined. Certainly,the area is ripe for investigation, for understand-ing these features might lead to the develop-ment of new treatments for muscle pain.

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9Mechanical Signal Transduction

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