Signaling in Muscle Contraction Ivana Y. Kuo 1 and Barbara E. Ehrlich 1,2 1 Department of Pharmacology, School of Medicine, Yale University, New Haven, Connecticut 06520 2 Department of Cellularand Molecular Physiology, School of Medicine, Yale University, New Haven, Connecticut 06520 Correspondence: [email protected]SUMMARY Signaling pathways regulate contraction of striated (skeletal and cardiac) and smooth muscle. Although these are similar, there are striking differences in the pathways that can be attributed to the distinct functional roles of the different muscle types. Muscles contract in response to depolarization, activation of G-protein-coupled receptors and other stimuli. The actomyosin fibers responsible for contraction require an increase in the cytosolic levels of calcium, which signaling pathways induce by promoting influx from extracellular sources or release from intracellular stores. Rises in cytosolic calcium stimulate numerous downstream calcium-de- pendent signaling pathways, which can also regulate contraction. Alterations to the signaling pathways that initiate and sustain contraction and relaxation occur as a consequence of exer- cise and pathophysiological conditions. Outline 1 Introduction 2 Skeletal muscle contraction 3 Skeletal muscle fiber types and exercise 4 Malignant hyperthermia in skeletal muscle 5 Cardiac muscle contraction 6 Exercise hypertrophy in cardiac muscle 7 Pathophysiological cardiac hypertrophy 8 Heart failure 9 Smooth muscle types 10 The contractile process in smooth muscle 11 Calcium sensitization 12 Vascular smooth muscle in disease 13 Concluding remarks References Editors: Lewis Cantley, Tony Hunter, Richard Sever, and Jeremy Thorner Additional Perspectives on Signal Transduction available at www.cshperspectives.org Copyright # 2015 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a006023 Cite this article as Cold Spring Harb Perspect Biol 2015;7:a006023 1 on July 28, 2018 - Published by Cold Spring Harbor Laboratory Press http://cshperspectives.cshlp.org/ Downloaded from
Transcript
Signaling in Muscle Contraction
Ivana Y. Kuo1 and Barbara E. Ehrlich1,2
1Department of Pharmacology, School of Medicine, Yale University, New Haven, Connecticut 065202Department of Cellular and Molecular Physiology, School of Medicine, Yale University, New Haven,Connecticut 06520
Signaling pathways regulate contraction of striated (skeletal and cardiac) and smooth muscle.Although these are similar, there are striking differences in the pathways that can be attributedto the distinct functional roles of the different muscle types. Muscles contract in response todepolarization, activation of G-protein-coupled receptors and other stimuli. The actomyosinfibers responsible for contraction require an increase in the cytosolic levels of calcium, whichsignaling pathways induce by promoting influx from extracellular sources or release fromintracellular stores. Rises in cytosolic calcium stimulate numerous downstream calcium-de-pendent signaling pathways, which can also regulate contraction. Alterations to the signalingpathways that initiate and sustain contraction and relaxation occur as a consequence of exer-cise and pathophysiological conditions.
Outline
1 Introduction
2 Skeletal muscle contraction
3 Skeletal muscle fiber types and exercise
4 Malignant hyperthermia in skeletal muscle
5 Cardiac muscle contraction
6 Exercise hypertrophy in cardiac muscle
7 Pathophysiological cardiac hypertrophy
8 Heart failure
9 Smooth muscle types
10 The contractile process in smooth muscle
11 Calcium sensitization
12 Vascular smooth muscle in disease
13 Concluding remarks
References
Editors: Lewis Cantley, Tony Hunter, Richard Sever, and Jeremy Thorner
Additional Perspectives on Signal Transduction available at www.cshperspectives.org
Copyright # 2015 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a006023
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Muscle can be subdivided into two general categories: stri-ated muscle, which includes skeletal and cardiac muscles;and nonstriated muscle, which includes smooth musclesuch as vascular, respiratory, uterine, and gastrointestinalmuscles. In all muscle types, the contractile apparatusconsists of two main proteins: actin and myosin. Striatedmuscle is so called because the regular arrangement ofalternating actomyosin fibers gives it a striped appearance.This arrangement allows coordinated contraction of thewhole muscle in response to neuronal stimulation througha voltage- and calcium-dependent process known as exci-tation–contraction coupling. The coupling enables therapid and coordinated contraction required of skeletalmuscles and the heart. Smooth muscle does not containregular striations or undergo the same type of excitation–contraction coupling. Instead, it typically uses second mes-senger signaling to open intracellular channels that releasethe calcium ions that control the contractile apparatus.These processes, in contrast to excitation–contraction cou-pling, are slow and thus suitable for the slower and moresustained contractions required of smooth muscle. Theactomyosin contractile apparatus is both calcium- and
phosphorylation-dependent, and restoration of basal cal-cium levels or its phosphorylation status returns an activelycontracting muscle to a noncontractile state. Muscle-spe-cific signals modulate these processes, depending on thetype of muscle, its function, and the amount of forcerequired.
In all muscle cells, contraction thus depends on an in-crease in cytosolic calcium concentration (Fig. 1). Calciumhas an extracellular concentration of 2–4 mM and a restingcytosolic concentration of �100 nM. It is also stored insidecells within the sarcoplasmic (SR, referring to skeletal andcardiac muscle) and endoplasmic reticulum (ER, referringto smooth muscle) at a concentration of �0.4 mM (Boot-man 2012). In striated muscle, the increase in calcium levelsis due to its release from the SR stores via ryanodine re-ceptor (RyRs). Neurotransmitters such as acetylcholinebind to receptors on the muscle surface and elicit a de-polarization by causing sodium/calcium ions to enterthrough associated channels. This shifts the resting mem-brane potential to a more positive value, which in turnactivates voltage-gated channels, resulting in an actionpotential (the “excitation” part). The action potential stim-ulates L-type calcium channels (also known as dihydropyr-idine receptors). In skeletal muscle, these are mechanically
coupled to the SR RyRs and open them directly. In cardiacmuscle, calcium influx through the L-type channels opensRyRs via calcium-induced calcium release (CICR) (Boot-man 2012). The RyR is a large tetrameric six-transmem-brane-span calcium-release channel. Of the three RyRsubtypes, RyR1 is predominantly found in skeletal muscle(see review by Klein et al. 1996), and RyR2 is predominant-ly found in cardiac muscle (Cheng et al. 1993).
Smooth muscle also contains voltage-gated calciumchannels and RyRs responsible for increases in intracel-lular calcium concentration (see below). Depolarizationcauses L-type calcium channels to open, enabling calciumto enter down its concentration gradient into the cell (Fig.1B). Opening of RyRs is usually associated with CICR.As the intracellular calcium concentration rises, calciumbinds to RyRs, whose consequent opening further en-hances the increase in cytoplasmic calcium concentration.Another major mechanism controlling contraction in thesecells, however, involves a different tetrameric six-trans-membrane-span calcium channel: the inositol 1,4,5-tri-sphosphate (IP3) receptor (IP3R). Circulating hormones(e.g., vasopressin and bradykinin) and neurotransmittersreleased by sympathetic nerves (e.g., endothelin and nor-epinephrine) act through G-protein-coupled receptors(GPCRs) to generate the second messenger IP3 via acti-vation of phospholipase C (PLC). IP3 binds to and opensIP3Rs on the ER/SR, causing the calcium release that drivescontraction. IP3Rs are present in both skeletal and cardiacmuscle; however, they do not contribute significantly to theexcitation–contraction coupling in striated muscle. Notethat both RyRs and IP3Rs are stimulated by low concentra-tions of cytoplasmic calcium but close when the concen-tration gets higher, showing bell-shaped response curves(Bezprozvanny et al. 1991; Finch et al. 1991).
Once intracellular calcium levels are raised, calciumbinds to either troponin C on actin filaments (in striatedmuscle) or calmodulin (CaM), which regulates myosin fil-aments (in smooth muscle). In striated muscle, calciumcauses a shift in the position of the troponin complex onactin filaments, which exposes myosin-binding sites (Fig.2A). Myosin bound by ADP and inorganic phosphate (Pi)can then form cross-bridges with actin, and the release ofADP and Pi produces the power stroke that drives contrac-tion. This force causes the thin actin filament to slide pastthe thick myosin filament and shortens the muscle. Bind-ing of ATP to myosin then releases myosin from actin, andmyosin hydrolyzes ATP to repeat the process (Fig. 2B).
In smooth muscle, by contrast, calcium binds to CaM,which then interacts with myosin light-chain kinase(MLCK), causing it to phosphorylate the myosin light-chain(MLC) at S19 or Y18. The phosphorylated MLC thenforms cross-bridges with actin, producing phosphorylated
actomyosin, which leads to contraction (Fig. 2C). Notethat striated muscle contraction can also be regulated bycalcium-bound CaM and MLCK; however, this is not thedominant mechanism. Finally, calcium and calcium-CaMalso bind to various other proteins in muscle cells, includ-ing the phosphatase calcineurin and protein kinases suchas CaMKIV, respectively. These regulate other cellular tar-gets, including transcription factors such as NFAT andCREB, which control gene expression programs that canhave longer-term effects on muscle physiology.
These different calcium-release mechanisms all alsostimulate the pumping of calcium from the cytoplasmback into intracellular stores via the SR/ER calcium ATPase(SERCA) pump. The plasma membrane calcium ATPase(PMCA) pump and the sodium/calcium exchanger(NCX), both of which reside on the plasma membrane,can also remove calcium from the cytosol. Calcium dis-sociates from troponin C or calmodulin as the cytosoliccalcium concentration decreases as a consequence, whichterminates the contraction process.
The main pathways promoting muscle relaxation in-volve the second messengers cAMP and cyclic guanosinemonophosphate (cGMP). cAMP is generated by adenylylcyclases, downstream from the b-adrenergic GS-coupledreceptor, which is activated by noradrenaline. Note thatthe cAMP pathway generally promotes contraction in car-diac muscle; however, in smooth muscle, activation ofcAMP causes relaxation. The cGMP pathway can be acti-vated either by nitric oxide (NO) or natriuretic peptides(NPs). In the case of blood vessels and other smooth mus-cles, NO produced by endothelial NO synthase (eNOS)diffuses across the muscle cell membrane to activate solu-ble guanylyl cyclase (sGC), which in turn increases levelsof cGMP. NPs, such as atrial (ANP, released by the heartatria under high blood pressure), brain (BNP, primarilyreleased by the heart ventricle), and c-type (CNP, mainlyinvolved in pathological conditions, and released by thevascular and central nervous system), instead bind to trans-membrane guanylyl cyclase, whose intracellular domainpossesses the enzymatic activity (Nishikimi et al. 2011).The cAMP and cGMP generated act via the protein ki-nase PKA and PKG on the contractile process in multipleways: (1) their phosphorylation of calcium pumps leadsto increased activity; (2) activation of MLC phosphatase(MLCP) by PKG antagonizes MLCK; and (3) both PKAand PKG cause a reduction in the sensitivity of the con-tractile machinery by inhibiting the GTPase RhoA (thisincreases MLCP activity and causes MLC dephosphoryla-tion and muscle relaxation). The levels of cAMP and cGMPare in turn regulated through their degradation by phos-phodiesterases to yield the inactive metabolites 5′-AMPand 5′-GMP.
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Below, we examine the key differences between the sig-naling mechanisms controlling contraction of skeletal,cardiac, and smooth muscle, and how these relate to theirdiffering functions. In addition, we discuss the changes tothe signaling pathways that occur as a consequence of ex-ercise and pathological situations.
2 SKELETAL MUSCLE CONTRACTION
Skeletal muscles comprise multiple individual muscle fi-bers that are stimulated by motor neurons stemming fromthe spinal cord. They are grouped together to form “mo-tor units” and more than one type of muscle fiber can be
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Figure 2. Calcium triggers contraction in striated muscle. (A) Actomyosin in striated muscle. (1) Striated muscle inthe relaxed state has tropomyosin covering myosin-binding sites on actin. (2) Calcium binds to troponin C, whichinduces a conformational change in the troponin complex. This causes tropomyosin to move deeper into the actingroove, revealing the myosin-binding sites. (B) Cross-bridge cycle in striated muscle. (1) Calcium binds to troponinC, causing the conformational shift in tropomyosin that reveals myosin-binding sites on actin. (2) ATP then binds tomyosin. (3) ATP is then hydrolyzed. (4) A cross-bridge forms and myosin binds to a new position on actin. (5) Pi isreleased and myosin changes conformation, resulting in the power stroke that causes the filaments to slide past eachother. (6) ADP is then released. (C) Contraction in smooth muscle. In smooth muscle, calcium binds to calmodulinand causes the activation of myosin light chain (MLC) kinase (MLCK). This phosphorylates MLC, which then bindsto actin to form phosphorylated actomyosin, enabling the cross-bridge cycle to start.
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present within each motor unit. Muscle fibers can be di-vided into fast- and slow-twitch muscles. Fast-twitch mus-cles use glycolytic metabolism and are recruited for phasicactivity (an active contraction). Slow-twitch muscles (alsoknown as red muscles) are rich in myoglobin, mitochon-dria, and oxidative enzymes and specialized for sustainedor tonic activity. See Schiaffino and Reggiani (2011) for amore complete discussion of skeletal muscle types and thetypes of myosin isoforms that make up fast- and slow-twitch muscles.
The neuromuscular junction (NMJ) that connects skel-etal muscle with the nerves that innervate them consistsof three distinct parts: the distal motor nerve ending, thesynaptic cleft, and the postsynaptic region, located on themuscle membrane. Motor neurons branch into multipletermini, which are juxtaposed to motor endplates, special-ized regions of muscle where neurotransmitter receptors
are concentrated (Fig. 3A). The transfer of informationbetween the nerve and muscle is mediated by the releaseof acetylcholine from the motor neuron, which diffusesacross the synaptic cleft, and binds to and activates theligand-gated, nicotinic acetylcholine receptors (nAChRs)on the endplate. Activation of the nAChR leads to an influxof cations (sodium and calcium) that causes depolarizationof the muscle cell membrane. This depolarization in turnactivates a high density of voltage-gated sodium channelson the muscle membrane, eliciting an action potential.
The action potential runs along the top of the mus-cle and invades the T-tubules (specialized invaginations ofthe membrane containing numerous ion channels). Theopening of voltage-gated sodium channels activates L-type voltage-gated calcium channels lining the T-tubule.A conformational change in these enables release of cal-cium on the closely apposed SR via activation of RyR1.
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Figure 3. Skeletal muscle contraction and changes with exercise. (A) Neurotransmitter (acetylcholine, ACh) releasedfrom nerve endings binds to receptors (AChRs) on the muscle surface. The ensuing depolarization causes sodiumchannels to open, which elicits an action potential that propagates along the cell. The action potential invades T-tubules and causes the L-type calcium channels to open, which in turn causes ryanodine receptors (RyRs) in the SRto open and release calcium, which stimulates contraction. Calcium is pumped back into the SR by (SR/ER calciumATPase SERCA) pumps. The decreasing cytosolic calcium levels cause calcium to disassociate from troponin C and,consequently, tropomyosin reverts to a conformation that covers the myosin-binding sites. (B) Signaling in exercisedskeletal muscle. Both calcium and calcium-independent signals stimulate the transcriptional coactivator PGC1a.This activates a number of transcription factors that regulate genes associated with mitochondrial biogenesis,glucose, and lipid homeostasis.
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Calcium then binds to troponin as described above, initi-ating the contraction process. Calcium-bound CaM alsoactivates MLCK, whose phosphorylation of the MLCchanges cross-bridge properties. This modulates the tropo-nin-dependent contraction, although there is no effect onthe ATPase activity of MLC. MLC phosphorylation insteadenhances force development at submaximal saturating cal-cium concentrations (see below). The phosphate group issubsequently removed by protein phosphatase 1 (PP1).
3 SKELETAL MUSCLE FIBER TYPES AND EXERCISE
Skeletal muscle is plastic. Exercise can lead to pronouncedchanges in its metabolic properties and, sometimes, achange in the fiber type. Physical differences betweenfast- and slow-twitch muscles underlie the functional rolesof these fibers, including the type of myosin used and dif-fering resting calcium levels. The free calcium level is two-fold higher in slow-twitch muscle, even though the SRvolume is greater. The level of MLC phosphorylation ishigher in fast-twitch muscle, however, because of higherlevels of expression of MLCK (Bozzo et al. 2005). The forceenhancement produced by MLC phosphorylation, undersubmaximal saturating calcium concentrations, counter-acts the reduction in force caused by fatigue in fast-twitchmuscle fibers (Schiaffino and Reggiani 2011).
Fast- and slow-twitch fibers also have different calcium-sequestering and -buffering systems. Different SERCA iso-forms are present: SERCA2A is the main isoform in slow-twitch muscle fibers, whereas SERCA1A is expressed infast-twitch muscle fibers. Similarly, different cytosolic cal-cium buffers are expressed. Calsequestrin (CSQ) is themain SR-luminal calcium-buffering protein. It is a high-capacity, low-affinity calcium-binding protein that bindscalcium cooperatively (Campbell et al. 1983). When themuscle is at rest, the SR is primed to release large amountsof calcium, because CSQ is polymerized, which reduces itsability to bind calcium. In cardiac muscle, only CSQ2 isexpressed. In skeletal muscle, CSQ1 and CSQ2 are found inslow-twitch muscle fibers, but only CSQ1 is found in fast-twitch muscle fibers. The two isoforms differ in their car-boxy-terminal tail; functionally, CSQ1 reduces the activityof RyR1, whereas CSQ2 increases the open probability ofRyR1 and RyR2 (Wei et al. 2009).
Other differences between the muscle fiber types in-clude posttranslational modifications such as phosphory-lation of RyR by PKA, and interactions between RyR andother proteins, such as CaM and FK506-binding protein(FKBP) 12 and FKBP12.6. Phosphorylation of RyR byeither PKA or CaMKII fully activates the channel. PKAand CaMKII can also phosphorylate phospholamban, aprotein that inhibits SERCA; phosphorylation causes
phospholamban to dissociate from SERCA. The FKBPsare immunophilins that bind to immunosuppressantssuch as rapamycin and FK506. FKBP12 and FKBP12.6have differing expression levels in muscle tissue, but bothbind all three forms of the RyR and stabilize its closed state.Collectively, these calcium-dependent differences betweenfast- and slow-twitch muscle fibers, in addition to differ-ences in the myosin isoform used and the number of mi-tochondria, account for the different functional outputs ofthe two muscle fiber types.
Long-term exercise causes a general shift in muscle fibertype from slow twitch to fast twitch. It induces a number ofchanges, including altered expression and activity of mem-brane transporters and mitochondrial metabolic enzymes,together with increased blood supply to skeletal muscle(Hardie 2012). These, in turn, enhance the oxidative ca-pacity and increase expression of enzymes preventing dam-age by reactive oxygen species (ROS). One major signalingpathway is through the peroxisome-proliferator-activatedreceptor (PPAR) g coactivator (PGC) 1a (Fig. 3B). PGC1acoactivates a number of transcription factors that regu-late genes important for muscle function. These includePPARs (which regulate glucose and lipid homeostasis, pro-liferation, and differentiation), nuclear respiratory factors(NRFs, which regulate metabolism and mitochondrialbiosynthesis), myocyte enhancer factor 2 (MEF2, whichis involved in development and hematopoesis), and Fork-head box O (FoxO) family transcription factors (whichcounter oxidative stress and promote cell-cycle arrest andapoptosis) (Handschin and Spiegelman 2006; Ronnebaumand Patterson 2010). In addition to PGC1a, calcium-de-pendent processes are also involved. Rises in cytosoliccalcium result in the activation of calcineurin, which thendephosphorylates NFAT. Translocation of NFAT to the nu-cleus results in activation of slow-fiber gene expression.Rises in nuclear calcium levels also cause calcium-depen-dent signaling molecules to become active. These includethe phosphorylation of histone deacetylases (HDACs) bynuclear calmodulin-dependent protein kinase. HDACs re-press transcription by causing DNA to be tightly wrappedaround histones. Removal of HDACs enables transcrip-tion factors such as MEF2 to bind and enable inductionof genes encoding proteins found in slow fibers (Liu et al.2005).
As mentioned above, exercise induces an increase inthe levels of mitochondrial metabolic enzymes to com-pensate for the increased metabolic demand on skeletalmuscle. Unsurprisingly, PGC1a is a potent stimulator ofmitochondrial biogenesis (see review by Olesen et al. 2010).This was shown elegantly by experiments in which over-expression of PGC1a in white, glycolytic skeletal musclecould turn it into red, oxidative muscle by increasing the
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levels and activity of a number of mitochondrial proteins(Lin et al. 2002; Wenz et al. 2009). These proteins includemost components of the mitochondrial respiratory chainand ATP synthase, as well as several enzymes in the Krebscycle and enzymes involved in fatty acid oxidation.
4 MALIGNANT HYPERTHERMIAIN SKELETAL MUSCLE
Mutations in RyR and CSQ isoforms cause malignanthyperthermia, demonstrating the importance of proteinsinvolved in calcium signaling in skeletal muscle. The mu-tations in RyR1 appear to increase its open probabilitywhen levels of luminal calcium are low and account forthe majority of malignant hyperthermia cases (80%); theremainder are caused by mutations to CSQ1.
In the case of RyR1 mutations, volatile anesthetics (in-haled anesthetics such as isoflurane or halothane) lead to arapid opening of RyR1 and an uncontrolled release of cal-cium from the SR, which in turn leads to sustained skeletalmuscle contraction (Robinson et al. 2006). In response tothe elevated calcium levels, there is activation of SERCA topump calcium, using ATP, back into the SR. However, thecontinual activation of SERCA consumes excessive ATP,leading to hypermetabolism. This then leads to a drop inATP levels, acidosis, tachycardia, and an abnormal increasein body temperature. These symptoms can be treated withdantrolene, an inhibitor of the RyR signaling pathway. Themutations in RyR1 associated with malignant hyperther-mia are clustered in three hot spots on the 500 kDa protein(Lanner et al. 2010). The first cluster is near the aminoterminus and the second cluster is in the middle of theprotein. The third cluster lies in the carboxy-terminal re-gion surrounding the channel-forming domains. How mu-tations in all three regions exert similar effects is yet to bedetermined.
Mutations in CSQ can also result in malignant hyper-thermia. A lack of buffering causes uncontrolled calciumtransients that lead to lethal malignant hyperthermia inresponse to heat stress and volatile anesthetics (Daineseet al. 2009).
5 CARDIAC MUSCLE CONTRACTION
In cardiac muscle, depolarization starts in the pacemakercells (modified cardiac myocytes that set the heart rate andare rich in signaling molecules) in the sinoatrial node,which is innervated by both parasympathetic and sympa-thetic nerves. The external stimuli modulate the activity ofthe pacemaker cells—they undergo spontaneous self-de-polarization to produce action potentials. This is achievedby a slow leak of potassium ions and a concurrent influx
of sodium and calcium ions. The action potential thentraverses to the cardiac myocytes, where it invades theT-tubule. However, unlike skeletal muscle, where L-typecalcium channels are directly coupled to RyRs, in cardio-myocytes the influx of calcium across the plasma mem-brane elicits calcium release from the SR via RyRs byCICR (Fig. 4B). The predominant isoform in the heart isRyR2. As in skeletal muscle, contraction is controlled byphosphorylation of troponin but can also be modulated bycalcium-CaM and MLCK. Mice with a nonphosphory-latable MLC in ventricular myocytes display depressedcontractile function and develop atrial hypertrophy anddilatation (Sanbe et al. 1999).
Catecholamines, such as adrenaline and noradrenaline,act on b-adrenergic receptors (metabotropic GPCRs) torelease cAMP that in turn activates PKA. PKA can beviewed as a primary regulator of the contractile pathway, asit phosphorylates a number of targets, including L-typecalcium channels and RyRs. In most cases, phosphory-lation of these proteins increases calcium release (forexample, phosphorylation of RyR increases its open prob-ability), and thus the outcome is to stimulate contraction(Ibrahim et al. 2011). Another target of PKA is phospho-lamban (an inhibitor of SERCA), which, when phosphor-ylated, loses its inhibitory effect on SERCA.
6 EXERCISE HYPERTROPHY IN CARDIAC MUSCLE
Cardiac hypertrophy is an abnormal enlargement of theheart that occurs because of increases in cell size and pro-liferation of nonmuscle cells. These changes can eitherbe beneficial (e.g., exercised hearts), in which changes arecorrelated with increased contractility, or detrimental, inwhich changes lead to decreased contractility and subse-quent heart failure.
Exercised hearts develop a form of mild cardiac hy-pertrophy that does not lead to cardiac failure. The mainstructural changes include a thickening of the ventricle wall,which leads to increased contractility and thus a greaterability to pump blood. Within myocytes, expression of theamyosin heavy chain increases, which leads to high ATPaseactivity and increased contractility (Fig. 4B). Various signalsare involved, including growth factors such as insulin-likegrowth factor (IGF1), vascular endothelial growth factor(VEGF), and hepatocyte growth factor (HGF) (Fig. 4B)(Hemmings and Restuccia 2012). There is increased signal-ing through the phosphoinositide 3 kinase (PI3K)/Aktpathway, which leads to proliferation and growth of cardio-myocytes (Matsui et al. 2003). Transcription factors up-regulated in exercised hearts include GATA4, which regu-lates genes involved in myocardial differentiation. Otherpathways, such as the calcineurin/NFAT pathway are
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down-regulated (Oliveira et al. 2009). Cardiac muscle, likeskeletal muscle, consumes tremendous amounts of ATP.Thus, PGC1a is also up-regulated in exercised hearts, facil-itating transcription of metabolic and oxidative genes (Ven-tura-Clapier et al. 2007; Watson et al. 2007).
7 PATHOPHYSIOLOGICAL CARDIACHYPERTROPHY
The main pathways driving pathological cardiac hypertro-phy are overstimulation of the sympathetic nervous system,
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Figure 4. Cardiac muscle contraction and changes with exercise. (A) Cardiac muscle contraction can occur as aconsequence of calcium entry through L-type calcium channels, which activate ryanodine receptor (RyR) channelsin the SR. Alternatively, b-adrenergic receptors on the cell membrane lead to activation of adenylyl cyclase (AC),which stimulates PKA. This can promote contraction by phosphorylating RyR and L-type calcium channels orrelaxation by phosphorylating the SERCA pump inhibitor phospholamban. (B) Changes with exercise lead to anactivation of the PI3K/Akt pathway, and a down-regulation of NFAT and calcinurin.
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increased oxidative stress, and inflammatory signaling (Ba-lakumar and Jagadeesh 2010). These collectively lead toinduction of fetal isoforms of heart proteins and a corre-sponding decrease in adult forms (Chien 1999), includingthe myosin heavy chain (see below). The signals responsibleinclude the GPCR agonist endothelin 1, peptide growthfactors such as platelet-derived growth factor (PDGF), epi-dermal growth factor (EGF), and cytokines such as cardio-trophin and leukemia inhibitory factor (LIF). Mechanicalstress can also induce hypertrophy. In each case, activationof the ERK mitogen-activated protein kinase (MAPK) path-way (Morrison 2012) is often observed in hypertrophy andleads to regulation of transcription factors that alter expres-sion of the myosin heavy chain, IP3R2, and other proteins(see below).
In hypertrophy, paracrine and autocrine neurohor-monal factors that activate the heterotrimeric G proteinGq, and consequently PLCb, are released. This resultsin an increase in cytosolic calcium levels and activationof PKC by diacylglycerol (DAG) as well as activation ofCaMKII (Mishra et al. 2010). The importance of the Gqpathway in hypertrophy has been shown in studies of trans-genic mice: mice overexpressing Gq have heart failure(D’Angelo et al. 1997), whereas mice with reduced Gq levelsare protected against hypertrophy (Wettschureck et al.2001). There is also a switch from the a form of the myosinheavy chain to the fetal b isoform (Miyata et al. 2000). Thishas a lower ATPase activity and a lower rate of contraction.Other changes include increased SERCA2A activity (Ha-senfuss et al. 1994; Meyer et al. 1995), up-regulation ofIP3R2 (Harzheim et al. 2010), and changes to a neuronalcalcium sensor (NCS1). NCS1 is a calcium-binding proteinthat also interacts with IP3R (Schlecker et al. 2006).
8 HEART FAILURE
The structural organization of the T-tubules breaks downin heart failure. This breakdown, caused by myocardialinsults (such as myocardial infarction causing ischemia)among other factors, leads to impaired contractility owingto reduced, asynchronous, and chaotic calcium release.Several signaling pathways are compromised in heart fail-ure. Initially, there can be reorganization of the b-adrener-gic system. Activation of the b2-adrenergic receptor isnormally limited to the T-tubule, whereas in heart failure,there is a redistribution of the receptor across the entireplasma membrane (Nikolaev et al. 2010). With chronicadrenergic activation, the hyperphosphorylation of RyRsresults in leaky RyR channels, leading to a reduction of SRcalcium and, thus, weaker contractions.
Other alterations to RyR2 that are observed includeincreased nitrosylation and loss of the regulatory protein
FKBP12.6 (Andersson and Marks 2010). Both of thesechanges result in increased RyR activity. Moreover, muta-tions in RyR2 that result in leaky channels have been linkedto catecholaminergic polymorphic ventricular tachycardia(CPVT) and arrhythmogenic right ventricular dysplasiatype 2.
Mutations in CSQ2 cause CPVT (Postma et al. 2002)by lowering buffering capacity within the SR, which resultsin premature calcium release and thus arrhythmias. Anoth-er important modulator of RyRs is junctin. Its levels arereduced in heart failure, which may be a compensatorymechanism to increase contractility (Pritchard and Kranias2009).
Heart failure also leads to up-regulation of moleculesthat may have a protective function. One pathway is throughcGMP, which promotes relaxation. The cGMP pathway isregulated by cGMP-targeted phosphodiesterases, of whichone, PDE5A, looks to be a promising target for protectivetherapy against hypertrophy.
9 SMOOTH MUSCLE TYPES
Smooth muscle is found lining the walls of various organsand tubular structures in the body, including the intestine,bladder, airway, uterus, blood vessels, and stomach. It re-ceives neural innervation from the autonomic nervoussystem, and its contractile state is also controlled by hor-monal and autocrine/paracrine stimuli. Smooth musclecan be divided into two types: unitary and multiunitsmooth muscles. In unitary smooth muscle, individualsmooth muscle cells are coupled to neighboring cells bygap junctions. These gap junctions permit cell-to-cell pas-sage of small molecules such as ATPand ions. These includethose mobilized in response to electrical signals causingdepolarization, which enable the whole area (known as asyncytium) to coordinate activity. In contrast, in multiunitsmooth muscle, cells are not coupled to each other and areintermingled with connective tissue. Smooth muscle canundergo tonic (sustained) or phasic contractions. In thecase of vascular smooth muscle, a sustained contraction isrequired to provide vessel tone. This enables the regulationof blood flow. Blood vessels are divided into the larger di-ameter conduit vessels (e.g., the thoracic aorta) and thesmaller diameter resistance vessels. The resistance bloodvessels display a myogenic response, in which increasingpressures over the physiological range (�70–100 mmHg)result in a sustained contractile state. However, overcon-striction of the vessels leads to hypertension (see below).Other smooth muscle, such as that found in the gut, in-cluding the stomach, small intestine, or gall bladder, showsvariable tone and rhythmic contractions known as slowwaves.
Signaling in Muscle Contraction
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The important distinction between striated muscle andsmooth muscle is that calcium mediates contraction byregulating the availability of actin filaments in striated mus-cle, whereas in smooth muscle MLC is the target (Fig. 5).The source of the increase in cytosolic calcium levels can beextracellular or intracellular, or a combination of the two.In the case of tonic constriction of blood vessels, a constantsupply of calcium comes from influx via the L-type calciumchannels. The resting membrane potential of smooth mus-cle (between 250 and 240 mV) is such that it lies in anoverlap (the window current) between the activation andinactivation curves of the L-type channel. Thus a small
population of the L-type channels is always open. An alter-natively spliced high-voltage-gated form of T-type chan-nels may also contribute to calcium influx (Kuo et al. 2011),along with stretch-activated channels residing on the plas-ma membrane, such as TRPC6.
In stomach muscle, the rhythmic contractions are dueto the activity of pacemaker cells, but activation of voltage-gated calcium channels can trigger calcium entry and con-traction. Sympathetic nerves run along the vascular smoothmuscle and can release stimuli such as acetylcholine, nor-epinephrine, angiotensin, and endothelin. Moreover, circu-lating blood factors such as cytokines and diffusible factorssuch as nitric oxide can also act on receptors in the plasmamembrane or cross the plasma membrane, respectively, toregulate pathways controlling intracellular calcium levels.
GPCR
PKC DAG Ca2+
Ca2+
ER store
Contraction
IP3R
PIP2
IP3
Gq
MLCP
CaM
PLCβ
Agonist (e.g., ATP, vasopressin)
PKG
cGMPGTP
GC
GC
NOANP
MLCK
Relaxation
MLC
MLC
ROCK
Rho
CPI-17
L-type Ca2+
channel
-P
Figure 5. Smooth muscle contraction. Calcium released by L-type calcium channels or IP3Rs downstream from Gq-coupled cell-surface receptors causes smooth muscle contraction. It binds to calmodulin (CaM) and the resultingcomplex stimulates myosin light-chain (MLC) kinase (MLCK). This phosphorylates MLC to promote contraction.A RhoA/ROCK pathway and a diacylglycerol (DAG) pathway contribute to calcium sensitization by altering thephosphorylation status of myosin light-chain phosphatase (MLCP). Relaxation is mediated through the cGMP/PKG pathway downstream from nitric oxide (NO) and agonists such as atrial natriuretic peptide (ANP).
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The activation of receptor-operated channels (ROCs) alsocauses calcium influx, which enables additional calciumrelease from intracellular stores. GPCRs activate PLCb togenerate IP3, which releases calcium via IP3Rs. In vascularsmooth muscle and the circular smooth muscle of the gut,the main isoform is IP3R1. Note, however, that there is someheterogeneity. In longitudinal smooth muscle of the gut,RyRs, rather than IP3Rs, are expressed. Agonists such ascholecystokinin bind to the GPCR cholecystokinin A recep-tor (CCK-AR), which activates phospholipase A2, which inturn produces arachidonic acid. Arachidonic acid (AA) canalso be generated through the cleavage of DAG. AA activateschloride channels, which depolarize the cell membrane,enabling the opening of voltage-gated calcium channelsand an initial influx of calcium. This calcium can eitheract directly on the RyR causing CICR or enable the releaseof cyclic ADP ribose, which interacts with RyRs to enhanceCICR.
In all smooth muscle, calcium-bound CaM then bindsto MLCK, stimulating phosphorylation of MLC, whichleads to muscle contraction. The necessity for MLCK hasbeen shown in MLCK-knockout mice, in which smoothmuscle MLC cannot be phosphorylated by other kinases(He et al. 2008; Zhang et al. 2010). The dephosphorylationof MLC is catalyzed by MLCP and a complex of the myosin-targeting protein MYPT1 and the phosphatase PP1 andresults in relaxation.
11 CALCIUM SENSITIZATION
Calcium sensitization is an essentially calcium-indepen-dent process that enables the amount of constriction insmooth muscle to be tuned by an alteration in the sensi-tivity of MLC to calcium (Fig. 5). This process enables themuscle to sustain a contraction once the initial calciumtransient has dissipated. There are two mechanisms forcalcium sensitization: a DAG-PLC-PKC pathway and aRhoA pathway (Lincoln 2007).
Diacylglycerol (DAG) is produced by PLCb down-stream from certain GPCRs and activates the conventionaland novel protein kinase C (cPKC and nPKC), but notatypical PKC (aPKC) (Steinberg 2008). PKC has a varietyof downstream targets, such as MLCK and C-kinase poten-tiated protein phosphatase 1 inhibitor, molecular mass17 kDa (CPI-17), both of which enhance constriction.CPI-17 is a smooth-muscle-specific inhibitor of MLCPthat binds to its catalytic subunit and inhibits phosphataseactivity, allowing contraction to persist.
Several agonists, including angiotensin II, norepine-phrine, and endothelin, activate the small G proteinRhoA. RhoA in turn activates Rho kinase (ROCK), whichcan mediate calcium sensitization through two main
pathways. First, ROCK stimulates phosphorylation ofMYPT1 (Feng et al. 1999). This can be direct, at T695 orT853, with a preference for T853. Alternatively, it can phos-phorylate another kinase, zipper-interacting protein kinase(ZIPK, also known as DAPK3), which phosphorylatesMYPT1 primarily at T695 (Kiss et al. 2002). ZIPK alsophosphorylates MLC at T18/S19. Phosphorylation ofMYPT1 interferes with binding of MLCP to MLC, andthus is believed to decrease phosphatase activity. ROCKcan also phosphorylate CPI-17 (MacDonald et al. 2001).
The preference for the MYPT1 or CPI-17 pathway de-pends on the type of smooth muscle. Whereas MYPT1 isubiquitously expressed in smooth muscle, CPI-17 is differ-entially expressed. Moreover, RhoA and associated proteinsare expressed at lower levels in phasic smooth muscle com-pared with tonic smooth muscle (Patel and Rattan 2006).Note that PKC can also phosphorylate CPI-17 to preventMLCP activity. Within resistance arteries, an increase invascular pressure also activates the RhoA pathway; how-ever, the signaling intermediates linking the change in vas-cular pressure and the activation of RhoA remain unknown(Cole and Welsh 2011).
12 VASCULAR SMOOTH MUSCLE IN DISEASE
Smooth muscle cells are remarkably plastic, altering theirphenotype in response to conditions such as vascular in-jury, altered blood flow conditions, or disease states. Thechanges in phenotype that can occur include cell prolifer-ation, apoptosis, and cell migration and are induced bymany factors, including cytokines and growth factors, me-chanical forces, neuronal stimuli, and genetic factors. Herewe limit our discussion to hypertension.
In hypertension, there is often a change in the sympa-thetic nervous system and the renin–angiotensin systemthat leads to increased blood pressure. Angiotensinogenis converted to angiotensin I by renin, which in turn isconverted to angiotensin II by angiotensin-converting en-zyme (ACE). Increased circulating angiotensin II acts onthe angiotensin receptors (AT1 and AT2), which, whenactivated, cause increased peripheral resistance. The con-sequence for smooth muscle cells is they become hy-percontractile. Treatments include ACE inhibitors (whichinhibit the conversion of angiotensin I to angiotensinII), a1-adrenergic antagonists (which block the AT1 andAT2 GPCRs), and calcium channel blockers (such as dihy-dropyridines, which inhibit the voltage-gated calciumchannels). All of these treatments aim to reduce the con-tractility of smooth muscle. Interfering with downstreamtargets such as RhoA signaling in hypertensive animals hasalso been shown to be effective (Uehata et al. 1997; Sekoet al. 2003; Moriki et al. 2004).
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The sustained contractile state of vascular smooth mus-cle is associated with the activation of calcium-dependenttranscription factors. These include SRF, FOS, NFAT,and CREB. SRF, which is activated by the RhoA pathway,promotes the expression of genes encoding componentsof the contractile apparatus. Calcium-stimulated CaMKIIactivates and causes the translocation of CaMKIV to thenucleus, where it can activate CREB, which promotes tran-scription of components of the contractile apparatus andother targets. However, CaMKII can also activate a phos-phatase that dephosphorylates and thus inactivates CREB(Matchkov et al. 2012). NFAT is activated on dephosphor-ylation by calcium-activated calcineurin, which inducesgenes associated with proliferation and migration.
NO produced by eNOS in endothelial cells protectsagainst the changes observed in hypertension: the cGMPpathway inhibits DNA synthesis, mitogenesis, and cellproliferation (Forstermann and Sessa 2012). However, en-dothelial dysfunction is a hallmark of vascular disease, in-cluding hypertension. In many types of vascular diseases,eNOS is up-regulated but owing to reduced oxygen avail-ability it is converted to a dysfunctional enzyme that pro-duces superoxides, which contribute to vascular oxidativestress (Forstermann and Sessa 2012).
In some disease states, smooth muscle cells adopt a non-contractile phenotype. Although these cells still have signal-ing machinery that increases intracellular calcium levels,they have significantly reduced calcium influx throughvoltage-gated calcium channels. Thus, there is a shift tointracellular-store-operated calcium release, similar to thechanges observed in cardiac hypertrophy. Concomitantwith decreases in the levels of SERCA, RyR2, PMCA1, andthe sodium/calcium exchanger, the levels of STIM, ORAI(proteins associated with refilling of intracellular cal-cium stores; see Bootman 2012), SERCA2B, and IP3R in-crease and there is a change in RyR receptor subtypesfrom RyR2 to RyR3 (Lipskaia and Lompre 2004; Berra-Romani et al. 2008; Baryshnikov et al. 2009; Matchkovet al. 2012). These changes collectively reflect a less contrac-tile phenotype.
13 CONCLUDING REMARKS
Signal transduction is essential for the function of con-tractile cells. The stimulatory signal results in an in-crease in cytosolic calcium levels, which activates musclecontraction. We now know the main contributors to thevarious types of muscle contraction, and have a better ap-preciation of the changes that occur to the contractileapparatus under exercise and pathophysiological condi-tions. For example, the identification of PGC1a as a masterregulator of transcription factors up-regulated in both
exercised and pathological striated muscle provides newavenues to modulate muscles in a therapeutic setting. It isalso apparent that many signaling proteins in both smoothand striated muscles are activated by changes in cytosol-ic calcium levels, and these signaling pathways often leadto alterations in gene expression. Because we now have abetter appreciation of the changes that occur to the con-tractile apparatus under pathophysiological conditions,this knowledge can be harnessed to allow us to treat diseasestrategically.
ACKNOWLEDGMENTS
Research in the Ehrlich Laboratory is supported by Nation-al Institutes of Health funds. I.Y.K. is an American HeartAssociation postdoctoral fellow.
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