signaling pathways in skeletal muscle remodeling

ANRV277-BI75-02 ARI 3 May 2006 9:5

Signaling Pathways inSkeletal Muscle RemodelingRhonda Bassel-Duby and Eric N. OlsonDepartment of Molecular Biology, University of Texas Southwestern Medical Center,Dallas, Texas 75390-9148; email: [email protected],[email protected]

Annu. Rev. Biochem.2006. 75:19–37

First published online as aReview in Advance onFebruary 15, 2006

The Annual Review ofBiochemistry is online atbiochem.annualreviews.org

doi: 10.1146/annurev.biochem.75.103004.142622

Copyright c© 2006 byAnnual Reviews. All rightsreserved

0066-4154/06/0707-0019$20.00

Key Words

myofiber, MEF2, calcineurin, calcium-dependent protein kinase,exercise adaptation, hypertrophy

AbstractSkeletal muscle is comprised of heterogeneous muscle fibers thatdiffer in their physiological and metabolic parameters. It is this di-versity that enables different muscle groups to provide a variety offunctional properties. In response to environmental demands, skele-tal muscle remodels by activating signaling pathways to reprogramgene expression to sustain muscle performance. Studies have beenperformed using exercise, electrical stimulation, transgenic animalmodels, disease states, and microgravity to show genetic alterationsand transitions of muscle fibers in response to functional demands.Various components of calcium-dependent signaling pathways andmultiple transcription factors, coactivators and corepressors havebeen shown to be involved in skeletal muscle remodeling. Under-standing the mechanisms involved in modulating skeletal musclephenotypes can potentiate the development of new therapeutic mea-sures to ameliorate muscular diseases.

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Calcineurin: aheterodimericprotein phosphatase(PP2B) comprised ofcalmodulin-bindingcatalytic A andregulatory B subunits

Contents

INTRODUCTION. . . . . . . . . . . . . . . . . 20PROPERTIES OF MYOFIBERS. . . . 21

Myofiber Diversity . . . . . . . . . . . . . . . 21Myofiber Adaptability . . . . . . . . . . . . 22

SIGNALING PATHWAYS INMYOFIBER REMODELING. . . . 22Myocyte Enhancer Factor-2 and

Histone Deacetylases . . . . . . . . . . 23Calcineurin/Nuclear Factor of

Activated T Cells . . . . . . . . . . . . . . 25Calcium/Calmodulin-Dependent

Protein Kinase, Protein KinaseC, and PKCmu/ProteinKinase D. . . . . . . . . . . . . . . . . . . . . . 26

Peroxisome Proliferator-ActivatedReceptor Delta andPeroxisome-Proliferator-Activated Receptor GammaCoactivator-1 alpha. . . . . . . . . . . . 27

Ras/Mitogen-Activated ProteinKinase . . . . . . . . . . . . . . . . . . . . . . . . 28

Insulin-Like Growth Factor, Akt,and Mammalian Target ofRapamycin . . . . . . . . . . . . . . . . . . . . 28

CLINICAL SIGNIFICANCE . . . . . . 29Muscular Dystrophy . . . . . . . . . . . . . . 29Type 2 Diabetes Mellitus and

Obesity . . . . . . . . . . . . . . . . . . . . . . . 30Muscle Atrophy . . . . . . . . . . . . . . . . . . 31Anabolic Steroids . . . . . . . . . . . . . . . . . 32

CONCLUSIONS. . . . . . . . . . . . . . . . . . . 32

INTRODUCTION

Skeletal muscle is composed of heteroge-neous specialized myofibers that enable thebody to maintain posture and perform a widerange of movements and motions. It is thisdiversity of myofibers that enables differentmuscle groups to fulfill a variety of func-tions. In addition to its obvious roles inmotility, skeletal muscle plays a central rolein the control of whole-body metabolism.

These seemingly different functions are con-trolled by signaling pathways that enablemuscle fibers to respond to the changingmetabolic and functional demands of theorganism.

The premise that myofibers remodel andmodify their phenotype was demonstratedover 45 years ago when cross-reinnervationstudies were shown to alter the contrac-tile properties of myofibers (1). Similarly,skeletal muscle responds to exercise train-ing by remodeling the biochemical, mor-phological, and physiological states of indi-vidual myofibers. The remodeling processprovides an adaptive response that servesto maintain a balance between physiologi-cal demands for contractile work and the ca-pacity of skeletal muscle to meet those de-mands. Many of the remodeling responsesinvolve activation of intracellular signalingpathways and consequent genetic repro-gramming, resulting in alterations of mus-cle mass, contractile properties, and metabolicstates.

Advances in genetic engineering have al-lowed the introduction or depletion of factorswithin the myofiber, facilitating the evaluationof signaling factors during muscle remod-eling. In particular, myofiber transforma-tion has successfully been achieved in trans-genic mouse models using muscle-specificpromoters to drive expression of calcineurin(protein phosphatase 2B) and various calcium-dependent kinases. Activation of specific sig-naling pathways in myofibers has profoundeffects, not only on contractile proteins, butalso on alterations of metabolic states lead-ing to changes in muscle performance. Be-cause of space limitations, this review doesnot discuss the pathways controlling mus-cle development (2) nor the contributionof satellite cells to skeletal muscle regen-eration (3) but focuses on the signalingmechanisms that modify myofiber functionwith emphasis on clinical significance andtherapeutic approaches to ameliorate musclediseases.

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PROPERTIES OF MYOFIBERS

The musculature of the body is composed ofa variety of muscle groups, such as soleus, ex-tensor digitorum longus, and plantaris. Eachmuscle group is comprised of heterogeneousmyofibers that differ in their biochemical,physiological, and metabolic parameters. Themyofiber content is a determinant of mus-cle heterogeneity in contraction speed and fa-tigue resistance. A striking feature of the my-ofiber is the ability to transform and remodelin response to environmental demands.

Myofiber Diversity

Although histologically skeletal muscle ap-pears uniform (Figure 1a), it is comprised ofmyofibers that are heterogeneous with respectto size, metabolism, and contractile function(4). On the basis of specific myosin heavy-chain isoform expression, myofibers are clas-sified into type I, type IIa, type IId/x, andtype IIb fibers, with types I and IIa exhibit-ing oxidative metabolism and types IIx and IIbbeing primarily glycolytic (5, 6). Type I my-ofibers, also termed slow-twitch fibers, exert aslow contraction owing to the ATPase activ-ity associated with the type I myosin. Slow-

Slow-twitchmyofibers: musclefibers that expresstype I myosin heavychain

Fast-twitchmyofibers: musclefibers expressingtype IIa, type IId/x,and type IIb myosinheavy chain

twitch myofibers are rich in mitochondria,have more capillaries surrounding each fiber,exhibit oxidative metabolism, have a low ve-locity of shortening, and have a high resis-tance to fatigue. Type II fibers, termed fast-twitch myofibers, exert quick contractions andfatigue rapidly. The slow oxidative fibers arerequired for maintenance of posture and tasksinvolving endurance, whereas fast-glycolyticfibers are required for movements involv-ing strength and speed. Different myofibersubtypes are detected during embryonic life(7), and patterning of fiber types within ma-jor muscle groups is established postnatally(8).

In addition to the variability seen in myosinheavy-chain gene expression, fiber-type dif-ferences are observed with the expressionprofile of other muscle proteins, such astropomyosin, myosin light chain, parvalbu-min, phospholambin, and sarcoplasmic retic-ulum calcium ATPase (SERCA). Althoughthere are multiple levels of distinction amongmyofibers, classically, fiber type is defined onthe basis of its myosin heavy-chain isoformexpression profile. Fiber type is determinedusing assays that delineate the differences inATPase activity that correlate with specificmyosin heavy-chain isoforms. The basis of the

Figure 1Heterogeneous distribution of skeletal muscle fibers. Fiber-type analysis of serial transverse sections ofmouse soleus by (a) hematoxylin and eosin stain showed a checkerboard pattern of fibers,(b) metachromatic dye-ATPase method showed type I fibers (stained dark blue) and type IIA (stained lightblue), and (c) immunohistochemistry using a monoclonal antibody recognized type I myosin heavy chain.The asterisks mark the same type I fibers in each panel.

www.annualreviews.org • Skeletal Muscle Remodeling 21

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Motor neuron: aneuron thatinnervates musclefibers

Signaltransduction: anextracellular signalstimulates a receptor,activating amessenger andchanging geneexpression andphenotype

reaction is the deposition of insoluble saltsof inorganic phosphate cleaved from ATPby myofibrillar ATPase(s) followed by sub-stitution of the phosphates with less solublechromogenic salts (9) (Figure 1b). Immuno-histochemistry using monoclonal antibodiesthat recognize isoform-specific myosin heavychain is another method used to determinefiber type (Figure 1c).

Slow-twitch oxidative myofibers (type I)are involved in sustained, tonic contractileevents and maintain intracellular calcium con-centrations at relatively high levels (100–300 nM) (10, 11). In contrast, fast-twitchglycolytic myofibers (type IIb) are used forsudden bursts of contraction and are charac-terized by brief, high-amplitude calcium tran-sients and lower ambient calcium levels (lessthan 50 nM) (12). These properties of skele-tal muscle fibers are dependent on the patternof motor nerve stimulation, such that tonicmotor neuron activity at low frequency (10–20 Hz) promotes the slow fiber pheno-type, whereas phasic motor neuron firing athigh frequency (100–150 Hz) results in fastfibers.

Myofiber Adaptability

The ability of skeletal muscle to remodel andchange phenotypically can be demonstratedby cross-innervation experiments in whichslow-twitch muscle (soleus) reinnervated withnerve fibers that normally supply fast-twitchmuscle (flexor digitorum longus) results inan increase in contractile speed. Conversely,innervation of fast-twitch muscle with nervefibers normally found on soleus muscle causesslower contraction (1). These studies estab-lished that specific impulse patterns deliveredby motor neurons exert a phenotypic influ-ence on the muscles they innervate and thatmyofibers are capable of remodeling. Furtherstudies using electrical stimulation to mod-ify neural activity delivered to a target mus-cle corroborate the cross-reinnervation databy showing predicted changes in myosin iso-

forms (13, 14). Exercise training also induceschanges in skeletal muscle by transform-ing the myofibers to an increased oxidativemetabolism and inducing fiber-type transi-tions from type IIb → type IId/x → type IIa →type I. To everyone’s chagrin, upon cessationof exercise training these myosin heavy-chainisoform transitions and metabolic changes arereversed.

Neuronal stimulation reprograms gene ex-pression in the myofiber primarily by usingcalcium as a second messenger. The in-put received from motor neurons via acetyl-choline receptors generates a depolarizationof the membrane, which reaches the sar-colemma transverse (T)-tubular membrane(15). The voltage-operated calcium channelor L-type calcium channel (the dihydropy-ridine receptor) in the T-tubules interactswith a skeletal muscle-specific sarcoplasmicreticulum calcium-release channel, the ryan-odine receptor (RyR1) (16). This physicalinteraction causes the RyR1 to open and re-lease calcium from the sarcoplasmic retic-ulum. The changes in intracellular calciumconcentrations determine muscle contractionand activate signaling pathways. The processof myofiber transformation is regulated bymultiple signaling pathways, many of whichconverge on each other, culminating in theactivation and, perhaps, repression of a myr-iad of genes involved in remodeling of skeletalmuscle.

SIGNALING PATHWAYS INMYOFIBER REMODELING

Myofibers respond to physiological andpathological signals by transforming and re-modeling to adapt to the environmentaldemands. This adaptation is accomplishedthrough signal transduction by which an ex-tracellular signal interacts with receptors atthe cell surface, activating factors in sig-naling pathways and ultimately remodelingthe myofiber by effecting a change in geneexpression.


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Myocyte Enhancer Factor-2 andHistone Deacetylases

It is well recognized that the myocyte en-hancer factor-2 (MEF2) transcription factors,in conjunction with multiple myogenic regu-latory factors, play a dominant role in mus-cle formation by activating muscle-specificgenes and that the MEF2/histone deacetylase(HDAC) signaling pathway plays an impor-tant role in the transformation of myofibersin response to intracellular calcium fluctua-tions incurred by the effects of external physi-ological signals (Figure 2). MEF2 is a muscle-enriched transcription factor that binds toan A/T-rich DNA sequence in the controlregions of numerous muscle-specific genes(17). There are four vertebrate MEF2 genes,

Myocyte enhancerfactor-2 (MEF2): afamily oftranscription factorsthat activatesmuscle-specificgenes

HDAC: histonedeacetylase

MEF2A, -B, -C, and -D, which are expressedin distinct, but overlapping, patterns duringembryogenesis and in adult tissues. In themouse, Mef2c gene expression is detected indeveloping skeletal muscle concomitant withactivation of the skeletal muscle differenti-ation gene program. High levels of MEF2proteins are clearly detectable in developingmuscle lineages during embryogenesis (18).MEF2A protein appears as cells enter thedifferentiation pathway, and MEF2C is ex-pressed late in the differentiation program.Studies in primary cell cultures of humanskeletal muscle cells showed that various stim-uli, such as addition of insulin, hydrogen per-oxide, osmotic stress, and activation of AMP-activated protein kinase (AMPK) resulted inactivation of MEF2D DNA binding (19).

RCAN1 Calcineurin Kinase(s)

14-3-3

NFAT

NFAT

MEF2

PGC-1

Muscle remodeling genes

AMPK

Signals

Ca2+

PP

P

Class II HDAC

Class II HDAC

P

ATPdepletion

Figure 2Signaling pathwaysactivate skeletalmuscle remodelinggenes. In response tophysiologicaldemands,intracellular calciumconcentration iselevated, activatingthe calcineurin/nuclear factor ofactivated T cells(NFAT) andMEF2/HDACsignaling pathways.In response toworkload, ATP isdepleted activatingAMPK.


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Figure 3Exercise stimulates transcriptional activation of MEF2. (a) Soleus fromsedentary MEF2 indicator mouse was stained with X-gal to detect lacZexpression. (b) Soleus from MEF2 indicator mouse subjected to three daysof voluntary wheel running was stained with X-gal to detect lacZexpression.

To monitor the transcriptional activity ofMEF2 in vivo, a transgenic MEF2 sensormouse that harbors a lacZ transgene un-der the control of three tandem copies ofthe MEF2 consensus DNA-binding site wasgenerated (20). During embryogenesis, thesemice express lacZ in developing cardiac, skele-tal, smooth muscle, and neuronal cells. Afterbirth, transgene expression is downregulated,although MEF2 protein levels are high, sug-gesting that MEF2 activity is repressed. A se-ries of studies showed that MEF2 activity iscontrolled through association with class IIHDACs, which bind to MEF2 and repressMEF2 activity (21–25). In response to vari-ous signals, HDAC kinases are activated andphosphorylate these HDACs, creating a dock-ing site for intracellular chaperone protein14-3-3 to bind HDAC and mask the nuclearlocalization sequence as well as induce a con-formational change in HDAC that unmasksa nuclear export sequence, causing HDAC toexit from the nucleus and promoting MEF2activity (26–28). Signal-dependent release ofclass II HDACs from MEF2 appears to playa role in skeletal muscle differentiation (22).Transitioning myofibers to a slow-twitch phe-notype, using 10-Hz electrical stimulation,translocates HDAC4 from the nucleus to thecytoplasm and increases MEF2 activity, fur-ther supporting the role of class II HDACsin signaling pathways during skeletal muscleremodeling (29).

To identify factors that stimulate MEF2activity, MEF2 sensor mice were subjected tovoluntary wheel running and electrical stimu-lation of the sciatic nerve (30). These stimulihave been shown to promote a substantial de-gree of fiber-type transformation (type IIb toIIa to I) and to upregulate expression of pro-teins associated with oxidative metabolism,such as myoglobin. Following these exerciseregimens, MEF2 is activated, as demonstratedby the expression of lacZ in the MEF2 sensormice (Figure 3).

Further studies on MEF2 activation byexercise showed that this response is blockedwhen cyclosporine A, an inhibitor of theserine/threonine protein phosphatase 2B,calcineurin, is administrated. In addition,crossing transgenic mice overexpressingactivated calcineurin in skeletal mice with theMEF2 sensor mice showed that MEF2 activ-ity was dramatically activated by calcineurinsignaling (30, 31). Furthermore, it was shownthat the activation of both the MEF2 andcalcineurin pathways promotes expression ofmuscle-specific genes, including myoglobin,myosin heavy chain, and slow troponin I (32, 33).These findings revealed cross talk betweenthe MEF2/HDAC and calcineurin signalingpathways and delineated a molecular pathwayin which calcineurin and MEF2 participate inthe adaptive mechanisms by which myofibersacquire specialized contractile and metabolicproperties as a function of changing patternsof muscle contraction induced by exercise(Figure 2).

Although many MEF2 gene targets areknown, signaling pathways downstream ofMEF2 are largely unknown. Analysis of thegene expression profile of mice lacking Mef2cidentified a decrease in expression of a novelMEF2-regulated gene encoding a muscle-specific protein kinase Stk23/Srpk3, belong-ing to the serine arginine protein kinase(SRPK) family, which phosphorylates ser-ine/arginine repeat-containing proteins (34).The Srpk3 gene is specifically expressed inthe heart and skeletal muscle from embryo-genesis to adulthood and is controlled by


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a muscle-specific enhancer with an essentialMEF2-binding site. When the Srpk3 geneis disrupted in mice, myofibers show an in-crease in centrally placed nuclei, a character-istic of many myopathies, and disorganizedintermyofibrillar network in type II fibers.Overexpression of Srpk3 in skeletal musclecauses severe myofiber degeneration and earlylethality. These findings show that SRPK-mediated signaling plays important roles inmuscle growth and homeostasis downstreamof muscle-specific transcription regulated byMEF2.

Calcineurin/Nuclear Factor ofActivated T Cells

Calcineurin, a heterodimeric protein phos-phatase comprised of a calmodulin-bindingcatalytic A subunit and a calcium-binding reg-ulatory B subunit, is specifically activated bysustained, low-amplitude calcium waves andis a sensor of contractile activity by sens-ing calcium fluctuations (35, 36). Signaling isinitiated by sustained, low-amplitude calciumwaves allowing calcium to bind calmodulin,which activates calcineurin via the regulatorysubunit (37). Upon activation, calcineurindephosphorylates nuclear factor of activatedT cells (NFAT), resulting in translocation ofNFAT from the cytoplasm to the nucleuswhere it associates with other transcriptionfactors to activate specific sets of calcium-dependent target genes (38) (Figure 2).Among the transcription factors that mayserve as an important partner for NFAT pro-teins in myocytes is MEF2 (17, 30, 31).

Overexpression of activated calcineurin inmyoblasts modulates myofiber gene expres-sion by activating a subset of genes, whichare associated with type I myofibers, suchas myoglobin and troponin I slow (32, 39).To examine the effect of calcineurin in vivo,transgenic mice, harboring a muscle creatinekinase promoter driving activated calcineurin,were generated and shown to upregulate en-dogenous oxidative proteins, such as myo-globin, in a dose-dependent manner and drive

NFAT: nuclearfactor of activated Tcells

fast to slow myofiber transformation (30, 40),supporting the role of the calcineurin/NFATpathway in myofiber remodeling. Additionalevidence of the role of the calcineurin/NFATpathway in fiber-type specificity is seen bya reduction in oxidative/slow type I fibersin mice lacking calcineurin A isoforms al-pha or beta (41). In addition, conditionalcalcineurin β1 knockout mice, lacking thecalcium-binding regulatory subunit specifi-cally in skeletal muscle, display dramatic de-ficiencies in both myosin heavy-chain typeI and IIa protein expression and a decreasein the number of slow fibers (42). These re-sults further demonstrate that calcineurin ac-tivity regulates the slow fiber program. No-tably, the conventional calcineurin A alpha orbeta knockout mice show a reduction in mus-cle weight; in contrast, no significant weightreduction was seen with the skeletal muscle-specific conditional knockout calcineurin β1mice. The difference observed in muscle massbetween these two calcineurin knockout linesis most likely attributable to the eliminationof calcineurin in all cells, including myo-genic progenitors and myoblasts, in the con-ventional calcineurin knockout mice, whereaselimination of calcineurin is restricted to post-differentiated myofibers in the mice lackingcalcineurin β1 specifically in skeletal muscle.

Further evidence for a role of calcineurinin maintenance of the slow fiber phenotypeis seen in the treatment of rats with cy-closporine A, an inhibitor of calcineurin ac-tivity, which results in an induction of gly-colytic enzymes and a decrease in slow typeI contractile proteins with a transformationtoward a fast phenotype (32, 43). These find-ings are further supported by a study show-ing that calcineurin inhibitors block upreg-ulation of type I isoforms of myosin in amuscle regenerating system (44) and in a pri-mary skeletal muscle cell culture (45), show-ing that calcineurin activity is required for in-duction and maintenance of the slow type Imyofiber gene program. Furthermore, stud-ies in mice have shown that NFAT activityis higher in slow compared to fast muscles


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Skeletal musclehypertrophy: anincrease in the size ofmuscle fiber, whichincreases musclemass

(46). Introduction of a synthetic peptide in-hibitor of calcineurin-mediated NFAT activa-tion into the soleus leads to downregulationof slow myosin heavy-chain expression andan upregulation of myosin heavy-chain typeIId/x (46). These results indicate that NFATactivity is required for maintenance of slowmyosin heavy-chain gene expression and po-tentially is involved in the repression of thefast myosin heavy-chain IIx gene. Althoughthe mechanism whereby calcineurin signal-ing induces the slow fiber gene via NFAT andMEF2 seems clear, it remains unclear how thefast fiber gene program is repressed by suchsignals.

Overexpression of a protein inhibitor ofcalcineurin, RCAN1 (previously known asMCIP-1) (47), has been shown to inhibit cal-cineurin activity in vivo. Stable mouse linescontaining a conditional RCAN1 transgenewere generated and crossed with a trans-genic mouse line containing a skeletal muscle-specific promoter driving Cre recombinase.This strategy results in the expression ofRCAN1 in skeletal muscle by using skeletalmuscle-specific Cre recombinase to excise aregion of DNA and place RCAN1 cDNA inthe open reading frame. Using this Cre-ONapproach, it was shown that the skeletal mus-cle of the mice overexpressing RCAN-1 hasa decrease in calcineurin activity compared towild-type mice (47), and most notably, thesetransgenic mice lack type 1 fibers. These find-ings show that calcineurin activity is essentialfor maintaining type I fibers.

In contrast, inconsistencies with the cal-cineurin/NFAT pathway model were shownby slow fiber-specific expression of a reportergene (luciferase) controlled by expression ofmutated forms of the slow troponin I pro-moter that lack NFAT- or MEF2-binding sites(48), and another group (49) showed that invivo injections of a plasmid expressing acti-vated calcineurin did not activate the slowmyosin light chain promoter in soleus or ex-tensor digitorum longus muscle. In addition,mice lacking NFATc2 or -c3 exhibit reducedmuscle fiber size or number, respectively, but

no significant change in the proportions offiber types (50, 51). However, multiple studieshave clearly shown and confirmed that skele-tal muscle hypertrophy is not dependent oncalcineurin activity (42, 52, 53).

Calsarcins, a family of sarcomeric pro-teins, have been identified as regulators of cal-cineurin by interacting with calcineurin andcolocalizing with the z-disk protein, alpha-actinin (54). Cell culture experiments demon-strate that calsarcin-1 suppresses calcineurinactivity in vitro. Mice deficient in calsarcin-1showed that in vivo calcineurin activity andsignaling are enhanced in striated muscle, in-dicating that the absence of calsarcin-1 re-lieves calcineurin inhibition (55). Consistentwith the hypothesis that calcineurin activ-ity promotes type I fibers, calsarcin-1 defi-cient mice show an increase in type I fibers.Through protein interactions, calsarcins serveto tether calcineurin to the sarcomere, plac-ing it in proximity to a unique intracellularcalcium pool where it can interact with spe-cific upstream activators and downstream sub-strates. These findings identify the sarcomereas a site of regulation of the calcineurin/NFATsignaling pathway, via calsarcin-1, and impli-cate the sarcomere as an active modulator ofmyofiber remodeling at the level of gene tran-scription.

Calcium/Calmodulin-DependentProtein Kinase, Protein Kinase C,and PKCmu/Protein Kinase D

Class II HDACs (HDAC4, HDAC5,HDAC7, and HDAC9) are highly expressedin skeletal muscle and directly bind MEF2,repressing expression of MEF2-dependentgenes. It has been shown that binding ofclass II HDACs to MEF2 is mediated by 18conserved amino acids in the amino-terminalextensions of class II HDACs, a domainthat is lacking in class I HDACs (56). Phos-phorylation of class II HDACs results intheir export from the nucleus and activationof MEF2-dependent genes (22), leading tomuscle remodeling. Because of the critical


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role of HDAC phosphorylation in regulatingmyocyte differentiation and remodeling,there has been intense interest in identifyingthe kinase(s) responsible for class II HDACnuclear export and inactivation in vivo.In vitro studies have shown that signalingby calcium/calmodulin-dependent proteinkinase (CaMK) results in phosphorylationof class II HDACs, promoting shuttlingof HDACs from the nucleus to the cyto-plasm and activation of MEF2 (22). Furtherevidence supporting the role of CaMK inskeletal muscle remodeling is seen whenaddition of a CaMK inhibitor, KN-62, blocksHDAC-green fluorescent protein (GFP)translocation from the nucleus to the cyto-plasm in response to slow fiber-type electricalstimulation in isolated myofibers (29). Inaddition, CaMKII is known to be sensitiveto the frequency of calcium oscillations (57)and is activated during hypertrophic growthand endurance adaptations (58). The notionthat CaMK is involved in muscle remodelingis supported by ectopically overexpressingCaMKIV in skeletal muscle and observing anincrease in type I fibers. However, CaMKIVis not expressed endogenously in skeletalmuscle, and mice lacking CaMKIV havenormal fiber-type composition with an in-crease in slow myosin heavy-chain isoform inthe soleus muscle (59). Therefore, althoughexogenous CaMKIV promotes transfor-mation of myofibers to a slow phenotype,it is unlikely that CaMKIV plays a role inphysiological skeletal muscle remodeling.Furthermore on the basis of a biochemicalassay for the HDAC kinase, there appears tobe another HDAC kinase that is induced inresponse to calcineurin signaling (at least inthe heart); this kinase is resistant to CaMKinhibitors and does not bind to calmodulin(60).

To further define the signaling pathwaysleading to the phosphorylation of class IIHDACs, the potential of multiple kinasepathways to stimulate HDAC5 nuclear exportwas examined and showed that the protein ki-nase C (PKC) pathway promotes nuclear ex-

PKC: proteinkinase C

PKD:PKCmu/proteinkinase D

port of HDAC5 by stimulating phosphoryla-tion of the 14-3-3 docking sites (61). Furtherstudies showed that PKCmu/protein kinaseD (PKD) acts as a downstream effector kinaseof PKC and stimulates the nuclear export ofHDAC5. On the basis of expression of PKDin skeletal muscle, in vitro studies, and trans-genic mouse lines (M.S. Kim, R. Bassel-Duby,and E.N. Olson, unpublished data), we specu-late that PKD is an important skeletal muscleHDAC kinase.

Exercise studies performed in humansshowed that atypical PKC isoforms (aP-KCzeta, -lambda, -mu), but not conventionalPKC isoforms (cPKCalpha, -beta1, -beta2,and -delta), are activated by exercise in con-tracting muscle (61a, 61b). These findingsare consistent with the transgenic mouse datashowing a role for PKDmu/PKD in skeletalmuscle remodeling and suggesting a poten-tial role for atypical PKC in the regulation ofskeletal muscle function and metabolism dur-ing exercise in both mice and humans.

Involvement of skeletal muscle signalingpathways is seen with other members of thePKC family. PKC-theta, a member of thenovel PKC subfamily, is the predominantPKC isoform expressed in skeletal muscle (62,63). In adult skeletal muscle, PKC-theta is ex-pressed primarily in type II glycolytic fibers(64). Studies using lipid emulsion infusionin rats showed that activation of PKC-thetais associated with skeletal muscle insulin re-sistance (65, 66). Most recently, mice lack-ing PKC-theta were shown to be protectedagainst fat-induced defects in skeletal muscleinsulin signaling (67), indicating that PKC-theta is a crucial component mediating fat-induced insulin resistance in skeletal muscle.

Peroxisome Proliferator-ActivatedReceptor Delta andPeroxisome-Proliferator-ActivatedReceptor Gamma Coactivator-1alpha

Enhanced oxidative capacity and metabolicefficiency of skeletal muscle is seen


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PGC-1α:peroxisome-proliferator-activatedreceptor-gammacoactivator-1

PPAR: peroxisomeproliferator-activatedreceptor

mTOR: mammaliantarget of rapamycin

IGF-1: insulin-likegrowth factor

following exercise training, in part ow-ing to a dramatic increase in mitochondrialcontent resulting from changes in the ex-pression of genes that increase mitochondrialbiogenesis. The transcriptional coactivatorperoxisome-proliferator-activated receptor-gamma coactivator-1 (PGC-1α) is considereda master regulator of mitochondrial geneexpression and has been shown to activatemitochondrial biogenesis and oxidativemetabolism (68–70). PGC-1α, expressed inbrown fat and skeletal muscle, is preferen-tially enriched in type I myofibers. Studiesperformed in humans and rodents show thatendurance exercise induces PGC-1α mRNAand protein expression (71–74). Skeletalmuscle-specific overexpression of PGC-1α

in transgenic mice resulted in an increasein type I fibers in white vastus and plantarismuscles (75). These transgenic mice alsoexhibited an increase in proteins involved inmetabolic oxidation and, most importantly,displayed an increase in muscle performanceand a decrease in muscle fatigue. Usingfiber-type-specific promoters, it was shownthat PGC-1α activates transcription incooperation with MEF2 proteins and servesas a target for calcineurin signaling, which hasbeen implicated in slow fiber gene expression.These findings indicate that PGC-1α is aprinciple factor modulating muscle fibertype and outline a combinatorial effect ofactivation of multiple signaling pathwaysevoked during skeletal muscle remodeling.

Peroxisome proliferator-activated recep-tor (PPAR) delta is a major transcriptionalregulator of fat burning in adipose tissuethrough activation of enzymes associated withlong-chain fatty-acid β-oxidation (76) andis the predominant PPAR isoform presentin skeletal muscle. PPAR delta was overex-pressed in skeletal muscle, resulting in a fiber-type switch to increase the number of ox-idative myofibers (77), and the mice withactivated PPAR delta showed an increasespecifically in type I fibers and the abilityto continuously run up to twice the distanceof wild-type littermates (78). Because PPARs

associate with PGC-1, it is conceivable thatexercise induction of PGC-1α may activatePPAR delta and induce myofiber remodeling.

Ras/Mitogen-Activated ProteinKinase

High-intensity exercise (79) and electro-stimulation (80) have been shown to acti-vate the Ras/mitogen-activated protein ki-nase (MAPK) pathway. In vivo studies showedthat Ras-dependent pathways affect both fibersize and fiber type (81). Introduction of ex-ogenous MAPK-activating Ras (RasV12S35)into denervated regenerating muscle fibers in-duced the expression of type I myosin heavychain but did not affect myofiber size. TheRas/MAPK pathway mediates the switch ina myosin heavy-chain gene induced by slowmotor neurons in regenerating muscle. Incontrast, activation of the PI3K/protein ki-nase B (Akt) pathway by Ras induces musclegrowth but does not alter fiber-type distri-bution, corroborating the studies performedwith overexpression of activated Akt in skele-tal muscle (82).

Insulin-Like Growth Factor, Akt, andMammalian Target of Rapamycin

As exemplified by the physique of a body-builder, skeletal muscle can adapt to work-load by changing myofiber size. Studies us-ing a functional overload model of the ratplantaris showed that the Akt/mammalian tar-get of rapamycin (mTOR) signaling path-way is activated during hypertrophy (52),corroborating studies that showed hypertro-phy of cultured myoblasts in response toinsulin-like growth factor (IGF-1) to be de-pendent on a PI3K/Akt/mTOR pathway (83)(Figure 4). Transgenic mice overexpressingconstitutively active Akt, specifically in skele-tal muscle, showed an increase in musclemass owing to an increase in muscle fibersize (84). Direct and indirect targets of Akt(also referred to as protein kinase B) in-clude mTOR and glycogen synthase kinase 3.


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P13K

Akt Akt

Proteindegradation

Proteinsynthesis

PHAS-14E-BP-1 Atrogin-1/

MAFbxP70S6K

Nucleus

FOXOmTOR

P

IGF-1 Insulin

Figure 4Signaling pathwaysin hypertrophy andatrophy. In responseto IGF, theAkt/mTORsignaling pathway isactivated.Phosphorylated AktphosphorylatesFOXO, inhibitingFOXO nuclear entry.Activation of mTORby Akt promotesprotein synthesis andincreases musclemass, resulting inhypertrophy. Indisease states, Akt isnot activated, andunphosphorylatedFOXO enters thenucleus and inducesthe muscle atrophyF-box(MAFbx)/atrogin-1/expression gene,promoting muscleatrophy.

mTOR is a kinase, sensitive to rapamycin,whose downstream targets, p70S6K and PHS-1/4E-BP1 increase protein translation initia-tion and elongation, promoting protein syn-thesis. Plantaris muscle from rats subjected tomuscle overload and treated with rapamycin,an inhibitor of mTOR activity, showed simi-lar activation of Akt in response to increasedworkload but did not show any change in myo-fiber size or weight, demonstrating that acti-vation of mTOR is necessary for skeletal mus-cle hypertrophy.

CLINICAL SIGNIFICANCE

Understanding the signaling pathways thatcontrol myofiber remodeling is pertinent toseveral important human diseases, includinginherited myopathies, systemic metabolic dis-eases, and common cardiovascular disorders.In muscular dystrophy, certain fibers are pref-

Skeletal muscleatrophy: a decreasein myofiber size,ultimatelygenerating a decreasein total muscle mass

erentially affected with degenerative changes;in diabetes, skeletal muscle contributes to ex-ercise intolerance; and in heart failure pa-tients, skeletal muscle atrophy is associatedwith a subgroup of patients at extremely highrisk. The factors in signaling pathways inmuscle remodeling may be viable therapeu-tic targets for the treatment of skeletal muscledisease.

Muscular Dystrophy

Duchenne muscle dystrophy (DMD) is a de-bilitating, life-threatening X-linked recessivemuscular disorder, caused by mutations in thedystrophin gene. A strategy used to allevi-ate DMD involves upregulation of utrophin,an autosomal homolog of dystrophin. Acti-vation of calcineurin stimulates the expres-sion of utrophin through an NFAT sitein the utrophin promoter (85). Moreover,


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GLUT4: glucosetransporter 4

overexpressing activated calcineurin in skele-tal muscle of mdx mice, lacking the dystrophingene, results in an increase in utrophin ex-pression, an increase in oxidative fibers, anda decrease in pathology, suggesting that ex-pression of exogenous calcineurin in skele-tal muscles provides substantial beneficialeffects on dystrophic muscle fibers (86). In ad-dition, it was observed that in skeletal muscleof DMD patients, fast myofibers are prefer-entially affected with degenerative changes,whereas slow myofibers are relatively spared(87). Introduction of calcineurin in skeletalmuscle not only activates utrophin expressionbut should also promote the formation of typeI fibers, displacing the fast fibers that are moreprone to damage. It will be of interest to exam-ine whether the induction of slow type I fibersis sufficient to ameliorate DMD. It is encour-aging that overexpressing IGF-1 within skele-tal muscles reduces the severity of the dystro-phy, demonstrating that modification of themyofiber has beneficial therapeutic effects inDMD (88).

Type 2 Diabetes Mellitus and Obesity

Skeletal muscle accounts for the majority ofinsulin-stimulated glucose uptake in humansand rodents. The insulin signaling pathwayin skeletal muscle is controlled by a series ofphosphorylation events linking initial activa-tion of the insulin receptor to downstreamsubstrates and ultimately translocating glu-cose transporter 4 (GLUT4) to the plasmamembrane to bind and uptake glucose. Amajor contributing factor to the progressivedevelopment of type 2 diabetes is reducedinsulin-stimulated whole-body glucose dis-posal, with the greatest defects attributed toskeletal muscle. Impaired insulin signal trans-duction (89) and defects in GLUT4 traffick-ing (90) are associated with skeletal muscleinsulin resistance in individuals with type 2 di-abetes. Fiber-type specific differences are seenin the insulin signal transduction pathway.In human skeletal muscle, insulin-stimulatedglucose transport directly correlates with the

percentage of slow-twitch muscle fibers, sug-gesting that a reduced skeletal muscle typeI myofiber population may be one compo-nent of a multifactorial process involved inthe development of insulin resistance (91). Infact, slow-twitch oxidative skeletal muscle hasgreater insulin binding capacity as well as in-creased insulin receptor kinase activity and au-tophosphorylation compared with fast-twitchglycolytic skeletal muscle (92). Furthermore,muscles with a greater percentage of oxidativemyofibers have a higher content of GLUT4(93). Overexpression of activated calcineurinin skeletal muscle of transgenic mice evokesan increase in type I myofibers and leads toimproved insulin-stimulated glucose uptake(in association with increased expression ofthe insulin receptor, Akt, and GLUT4) com-pared to wild-type littermates (94). Interest-ingly, such mice are protected against glucoseintolerance when maintained on a high-fatdiet. These results validate calcineurin as atarget to improve insulin signal transduction,enhance GLUT4 to correct glucose transportdefects, and improve glucose homeostasis indiabetic individuals.

A non-insulin-dependent pathway regu-lating glucose transport and GLUT4 translo-cation to the plasma membrane and T-tubules in skeletal muscle involves AMPKa heterotrimeric protein that senses in-creases in AMP-to-ATP and creatine-to-phosphocreatine ratios via a mechanism thatinvolves allosteric and phosphorylation mod-ifications (95). AMPK is activated in skeletalmuscle in response to exercise, phosphorylat-ing target proteins along diverse metabolicpathways, resulting in an increase of ATP-generating pathways, such as glucose uptakeand fatty-acid oxidation (96, 97). Studies us-ing AICAR, a pharmacological activator ofAMPK, in addition to transgenic overexpres-sion of dominant-negative mutants of AMPKshowed conclusively that AMPK activationincreases skeletal muscle glucose transportby translocating GLUT4 to the membrane,comparable to the effect seen with exercise.These findings point to the AMPK pathway


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as a potential target for therapeutic strategiesto restore metabolic balance to type 2 diabeticpatients.

Differences in muscle fiber compositionmay also play a role in determining suscep-tibility to dietary obesity. Skeletal muscle inobese individuals exhibits reduced oxidativecapacity, increased glycolytic capacity, and adecreased percentage of type I fibers (91, 98).PPARs comprise a family of nuclear hormonereceptors that mediate the transcriptional ef-fects of fatty acids and fatty-acid metabolites.Transgenic mice overexpressing PPAR deltain skeletal muscle exhibited an increase in ox-idative myofibers and a reduction in adipocytesize (99). Treatment of mice with the PPARdelta agonist GW501516 promoted an in-crease in expression of genes involved in ox-idative fibers and mitochondrial biogenesis(78), and transgenic mice overexpressing ac-tivated PPAR delta in skeletal muscle kept ona high-fat diet gained 50% less weight thanwild-type littermates, implying that expres-sion of PPAR delta in skeletal muscle has aprotective role against obesity.

Muscle Atrophy

Muscle atrophy is defined as a decrease inmyofiber size, ultimately generating a de-crease in total muscle mass, resulting fromdisuse, disease, or injury. Sarcopenia is an age-related chronic loss of muscle and strength;and cachexia is a form of muscle atrophy as-sociated with muscle disease or damage to thenerve associated with the muscle, commonlyleading to severe muscle wasting. Atrophicmyofibers have a smaller cross-sectional areathan normal myofibers and generate a reducedforce. However, they generally do not un-dergo apoptosis but retain most of the struc-tural features of normal muscle. There ismuch interest in understanding the signalingpathways that mediate atrophy in order to de-sign therapies to inhibit these pathways andultimately to alleviate muscle atrophy. Geneexpression profiling of muscles harvestedfrom multiple atrophy mouse models iden-

MuRF: muscle ringfinger

tified two genes, muscle ring finger (MuRF)1and muscle atrophy F-box (MAFbx)/atrogin-1,to be upregulated in atrophied muscle (100–102), and genetic deletion of these genes par-tially alleviated muscle atrophy. Both MuRF1and atrogin-1/MAFbx proteins are E3 ubiqui-tin ligases responsible for the substrate speci-ficity of ubiquitin conjugation as part of theATP-dependent ubiquitin-proteosome pro-teolysis pathway involved in protein break-down and degradation, which may conceiv-ably result in a decrease of myofiber size.Interestingly, FOXO transcription factors,substrates of Akt, have been shown to induceatrogin-1/MAFbx expression (103, 104), con-necting the molecular mediators of atrophyand the IGF-1/PI3K/Akt hypertrophy path-way (Figure 4). In the presence of IGF-1,PI3K/Akt is activated and phosphorylatesFOXO, preventing it from entering the nu-cleus to activate atrophy-related genes. Skele-tal muscle hypertrophy, following administra-tion of IGF-1, is mediated by an increase inprotein synthesis owing to Akt-induced phos-phorylation, activation of mTOR, as well asa lack of MAFbx/atrogin-1 expression causedby Akt-induced phosphorylation of FOXOand nuclear exclusion. Muscle disuse leads toa reduction in PI3K/Akt activity and a de-crease in FOXO phosphorylation, triggeringnuclear import of FOXO and activation of theatrogin-1/MAFbx.

NF-κB, a mediator of cytokine tumornecrosis factor (TNF) alpha during the in-flammatory response, is activated during mus-cular disuse. Myofibers treated with TNFplus interferon-gamma fail to maintain con-tractile activities and show significant reduc-tions in both MyoD and myosin heavy-chaingene expression, suggesting NF-κB involve-ment in cachexia by suppression of muscle-specific gene expression (105). Other studiesusing two separate mouse models, one de-signed to activate NF-κB and the other toinhibit NF-κB activity selectively in skeletalmuscle, demonstrated that activation of theNF-κB pathway is sufficient to induce severeskeletal atrophy, resembling cachexia (106).


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Interestingly, it was shown that activation ofNF-κB in muscle promotes proteolysis, as ev-idenced by elevated MuRF1 transcripts andprotein levels, but does not activate cytokinesignaling (106). Blocking the NF-κB pathwaywas shown to ameliorate muscle atrophy, sug-gesting new drug targets for clinical interven-tion during cachexia and other skeletal muscleatrophies.

Short periods of myofiber dennervationand muscle disuse provoke muscle atrophy,which in certain cases is reversible, leadingto the concept of compensatory mechanismsto sustain myofiber composition followinglimited episodes of inactivity. Expression ofRunx1, a DNA-binding protein, is stronglyinduced following myofiber denervation (100,107). Using mice lacking Runx1 specifically inskeletal muscle, it was shown that expressionof Runx1 is required to sustain denervatedmuscles from undergoing autophagy and se-vere muscle wasting (108).

A novel transcription factor named Mus-TRD1 (muscle TFII-I repeat domain-containing protein 1) was isolated becauseof its ability to bind the enhancer region ofthe troponin I slow gene (109). There are 11mouse MusTRD isoforms, and studies haveshown that MusTRD1 can act as a repres-sor of the troponin I (TnI) slow enhancer. Itis hypothesized that modulation of the Mus-TRD isoform content within muscle fibersprovides a means of differentially regulatingdownstream target genes in muscles of differ-ent fiber composition.

Anabolic Steroids

A timely issue in muscle remodeling is theuse of androgens as anabolic agents to in-crease skeletal muscle mass and reduce bodyfat. Testosterone effects on skeletal musclemass are dose dependent, with administrationof supraphysiological doses leading to a sub-stantial increase in muscle size and strength.Androgen receptors reside in muscle cells andmost likely mediate the response to andro-gens. Interestingly, studies determining the

effects of testosterone on muscle performanceshowed that testosterone administration is as-sociated with an increase in leg power andstrength but showed no change in muscle fati-gability and no change in specific tension,indicating that testosterone-induced gains inmuscle strength are reflective of an increaseof muscle mass (110). The increase in mus-cle mass is hypertrophic growth, as it is as-sociated with an increase in myofiber cross-sectional area, observed both in type I andtype II myofibers (111) and is not due to an in-crease in the number of myofibers. No signif-icant transition of myofiber specificity is seenbecause the relative proportion of type I andtype II fibers does not change after adminis-tration of testosterone. In addition, no changeis observed in the number of fibers per unit ofmuscle; however, an increase in myonuclearnumber is apparent and is hypothesized to beattributable to fusion with satellite cells (111).A study showing the long-term effects (about10 years) of anabolic steroids on high-levelpower-lifter athletes showed a larger myofiberarea with more myonuclei per fiber and morecentralized nuclei in athletes using steroids(112). In addition, no differences were seenwith regard to fiber-type proportions; how-ever, the type I fibers had 61% larger area,and the type II fibers had a 44% larger areathan athletes without steroids.

CONCLUSIONS

We are advised by physicians, family mem-bers, and various government agencies to im-prove our health status by exercising. Dur-ing exercise, the motor neuron is stimulated,resulting in activation of multiple signalingpathways in the myofibers and remodelingskeletal muscle to adapt to the physiologi-cal demand. Great strides have been madein animal models to understand the signal-ing pathways involved in muscle remodeling.However, whether these signaling pathwaysare physiologically valid in humans needs tobe confirmed, and the identity of additionaltranscription factors and target genes remains


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to be determined. Using multiple approaches,it has been elegantly shown that various com-ponents of signaling pathways promote fiber-type transitions, and it will be challenging andinformative to determine how these pathwaysintercalate and connect to remodel myofibers.Once further advances are made, we will de-pend on somatic cell delivery systems to target

muscle fibers and provide components thathave been shown to reduce the severity ofmuscular and metabolic diseases. In the fu-ture, exercising might mean taking a “pill” toactivate skeletal muscle remodeling via signal-ing pathways. But for now, it is no pain, nogain. Keep on running! Remember, it is bet-ter to burn out than fade away.

SUMMARY POINTS

1. Skeletal muscle is comprised of a complex array of heterogeneous muscle fibers thatdiffer in their physiological and metabolic parameters.

2. In response to environmental demands, skeletal muscle remodels and changes phe-notypically in order to sustain muscle performance.

3. Skeletal muscle remodels by activating signaling pathways to reprogram gene expres-sion.

4. Changes in calcium-dependent signaling pathways play key roles in regulating musclegrowth and metabolism.

5. Genetic and pharmacological modulation of skeletal muscle signaling pathways offertherapeutic opportunities for the treatment of muscle diseases.

FUTURE ISSUES TO BE RESOLVED

1. Many of the defined signaling pathways in skeletal muscle remodeling have beendetermined using transgenic or knockout mouse models. Confirmation is needed todetermine whether these signaling pathways are physiologically valid and are involvedin humans.

2. Although many signaling pathways have been identified in remodeling skeletal muscle,it remains unclear how these pathways are initiated by the motor neuron and how thepathways are intercalated.

3. The identity of additional transcription factors and target genes that are involved inskeletal muscle remodeling remains to be determined.

4. Discovery of a skeletal muscle somatic cell delivery system is needed to target musclefibers and provide components that have been shown to reduce the severity of muscularand metabolic diseases.

ACKNOWLEDGMENTS

We thank Alisha Tizenor and John M. Shelton for assistance with the figures.

LITERATURE CITED

1. Buller AJ, Eccles JC, Eccles RM. 1960. J. Physiol. 150:407–392. Buckingham M, Bajard L, Chang T, Daubas P, Hadchouel J, et al. 2003. J. Anat. 202:59–

68


Ann

u. R

ev. B

ioch

em. 2

006.

75:1

9-37

. Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

LIB

RA

RY

CO

NT

INU

AT

ION

S on

06/

07/0

6. F

or p

erso

nal u

se o

nly.

ANRV277-BI75-02 ARI 3 May 2006 9:5

3. Charge SB, Rudnicki MA. 2004. Physiol. Rev. 84:209–384. Williams RS, Neufer PD. 1996. In The Handbook of Physiology. Exercise: Regulation and

Integration of Multiple Systems, ed. LB Rowell, JT Shepherd, pp. 1124–50. Bethesda, MD:Am. Physiol. Soc.

5. Pette D, Staron RS. 2000. Microsc. Res. Tech. 50:500–96. Schiaffino S, Reggiani C. 1996. Physiol. Rev. 76:371–4237. Stockdale FE. 1997. Cell Struct. Funct. 22:37–438. Garry DJ, Bassel-Duby RS, Richardson JA, Grayson J, Neufer PD, Williams RS. 1996.

Dev. Genet. 19:146–569. Ogilvie RW, Feeback DL. 1990. Stain Technol. 65:231–41

10. Chin ER, Allen DG. 1996. J. Physiol. 491(Pt. 3):813–2411. Hennig R, Lomo T. 1985. Nature 314:164–6612. Westerblad H, Allen DG. 1991. J. Gen. Physiol. 98:615–3513. Lomo T, Westgaard RH, Dahl HA. 1974. Proc. R. Soc. London Ser. B 187:99–10314. Salmons S, Vrbova G. 1969. J. Physiol. 201:535–4915. Berchtold MW, Brinkmeier H, Muntener M. 2000. Physiol. Rev. 80:1215–6516. Murayama T, Ogawa Y. 2002. Trends Cardiovasc. Med. 12:305–1117. Black BL, Olson EN. 1998. Annu. Rev. Cell. Dev. Biol. 14:167–9618. Subramanian SV, Nadal-Ginard B. 1996. Mech. Dev. 57:103–1219. Al-Khalili L, Chibalin AV, Yu M, Sjodin B, Nylen C, et al. 2004. Am. J. Physiol. Cell

Physiol. 286:C1410–1620. Naya FJ, Wu C, Richardson JA, Overbeek P, Olson EN. 1999. Development 126:2045–5221. Lu J, McKinsey TA, Zhang CL, Olson EN. 2000. Mol. Cell 6:233–4422. McKinsey TA, Zhang CL, Lu J, Olson EN. 2000. Nature 408:106–1123. Miska EA, Karlsson C, Langley E, Nielsen SJ, Pines J, Kouzarides T. 1999. EMBO J.

18:5099–10724. Wang AH, Bertos NR, Vezmar M, Pelletier N, Crosato M, et al. 1999. Mol. Cell. Biol.

19:7816–2725. Lemercier C, Verdel A, Galloo B, Curtet S, Brocard MP, Khochbin S. 2000. J. Biol. Chem.

275:15594–9926. McKinsey TA, Zhang CL, Olson EN. 2000. Proc. Natl. Acad. Sci. USA 97:14400–527. Kao HY, Verdel A, Tsai CC, Simon C, Juguilon H, Khochbin S. 2001. J. Biol. Chem.

276:47496–50728. Wang AH, Kruhlak MJ, Wu J, Bertos NR, Vezmar M, et al. 2000. Mol. Cell. Biol. 20:6904–

1229. Liu Y, Randall WR, Schneider MF. 2005. J. Cell Biol. 168:887–9730. Wu H, Rothermel B, Kanatous S, Rosenberg P, Naya FJ, et al. 2001. EMBO J. 20:6414–2331. Wu H, Naya FJ, McKinsey TA, Mercer B, Shelton JM, et al. 2000. EMBO J. 19:1963–7332. Chin ER, Olson EN, Richardson JA, Yang Q, Humphries C, et al. 1998. Genes Dev.

12:2499–50933. Friday BB, Mitchell PO, Kegley KM, Pavlath GK. 2003. Differentiation 71:217–2734. Nakagawa O, Arnold M, Nakagawa M, Hamada H, Shelton JM, et al. 2005. Genes Dev.

19:2066–7735. Crabtree GR. 1999. Cell 96:611–1436. Dolmetsch RE, Xu K, Lewis RS. 1998. Nature 392:933–3637. Dolmetsch RE, Lewis RS, Goodnow CC, Healy JI. 1997. Nature 386:855–5838. Rao A, Luo C, Hogan PG. 1997. Annu. Rev. Immunol. 15:707–4739. Delling U, Tureckova J, Lim HW, De Windt LJ, Rotwein P, Molkentin JD. 2000. Mol.

Cell. Biol. 20:6600–11


Ann

u. R

ev. B

ioch

em. 2

006.

75:1

9-37

. Dow

nloa

ded

from

arj

ourn

als.

annu

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view

s.or

gby

LIB

RA

RY

CO

NT

INU

AT

ION

S on

06/

07/0

6. F

or p

erso

nal u

se o

nly.

ANRV277-BI75-02 ARI 3 May 2006 9:5

40. Naya FJ, Mercer B, Shelton J, Richardson JA, Williams RS, Olson EN. 2000. J. Biol.Chem. 275:4545–48

41. Parsons SA, Wilkins BJ, Bueno OF, Molkentin JD. 2003. Mol. Cell. Biol. 23:4331–4342. Parsons SA, Millay DP, Wilkins BJ, Bueno OF, Tsika GL, et al. 2004. J. Biol. Chem.

279:26192–20043. Bigard X, Sanchez H, Zoll J, Mateo P, Rousseau V, et al. 2000. J. Biol. Chem. 275:19653–

6044. Serrano AL, Murgia M, Pallafacchina G, Calabria E, Coniglio P, et al. 2001. Proc. Natl.

Acad. Sci. USA 98:13108–1345. Higginson J, Wackerhage H, Woods N, Schjerling P, Ratkevicius A, et al. 2002. Pflugers

Arch. 445:437–4346. McCullagh KJ, Calabria E, Pallafacchina G, Ciciliot S, Serrano AL, et al. 2004. Proc.

Natl. Acad. Sci. USA 101:10590–9547. Oh M, Rybkin II, Copeland V, Czubryt MP, Shelton JM, et al. 2005. Mol. Cell. Biol.

25:6629–3848. Calvo S, Venepally P, Cheng J, Buonanno A. 1999. Mol. Cell. Biol. 19:515–2549. Swoap SJ, Hunter RB, Stevenson EJ, Felton HM, Kansagra NV, et al. 2000. Am. J.

Physiol. Cell Physiol. 279:C915–2450. Horsley V, Friday BB, Matteson S, Kegley KM, Gephart J, Pavlath GK. 2001. J. Cell

Biol. 153:329–3851. Kegley KM, Gephart J, Warren GL, Pavlath GK. 2001. Dev. Biol. 232:115–2652. Bodine SC, Stitt TN, Gonzalez M, Kline WO, Stover GL, et al. 2001. Nat. Cell Biol.

3:1014–1953. Dupont-Versteegden EE, Knox M, Gurley CM, Houle JD, Peterson CA. 2002. Am. J.

Physiol. Cell Physiol. 282:C1387–9554. Frey N, Richardson JA, Olson EN. 2000. Proc. Natl. Acad. Sci. USA 97:14632–3755. Frey N, Barrientos T, Shelton JM, Frank D, Rutten H, et al. 2004. Nat. Med. 10:1336–4356. McKinsey TA, Zhang CL, Olson EN. 2001. Curr. Opin. Genet. Dev. 11:497–50457. De Koninck P, Schulman H. 1998. Science 279:227–3058. Chin ER. 2004. Proc. Nutr. Soc. 63:279–8659. Akimoto T, Ribar TJ, Williams RS, Yan Z. 2004. Am. J. Physiol. Cell Physiol. 287: C1311–

1960. Zhang CL, McKinsey TA, Chang S, Antos CL, Hill JA, Olsen EN. 2000. Cell 110:479–8861. Vega RB, Harrison BC, Meadows E, Roberts CR, Papst PJ, et al. 2004. Mol. Cell. Biol.

24:8374–8561a. Rose AJ, Michell BJ, Kemp BE, Hargreaves M. 2004. J. Physiol. 561:861–7061b. Perrini S, Henriksson J, Zierath JR, Widegren U. 2004. Diabetes 53:21–24

62. Chang JD, Xu Y, Raychowdhury MK, Ware JA. 1993. J. Biol. Chem. 268:14208–1463. Osada S, Mizuno K, Saido TC, Suzuki K, Kuroki T, Ohno S. 1992. Mol. Cell. Biol.

12:3930–3864. Donnelly R, Reed MJ, Azhar S, Reaven GM. 1994. Endocrinology 135:2369–7465. Griffin ME, Marcucci MJ, Cline GW, Bell K, Barucci N, et al. 1999. Diabetes 48:1270–7466. Yu C, Chen Y, Cline GW, Zhang D, Zong H, et al. 2002. J. Biol. Chem. 277:50230–3667. Kim JK, Fillmore JJ, Sunshine MJ, Albrecht B, Higashimori T, et al. 2004. J. Clin. Investig.

114:823–2768. Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM. 1998. Cell 92:829–

3969. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, et al. 1999. Cell 98:115–24


Ann

u. R

ev. B

ioch

em. 2

006.

75:1

9-37

. Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

LIB

RA

RY

CO

NT

INU

AT

ION

S on

06/

07/0

6. F

or p

erso

nal u

se o

nly.

ANRV277-BI75-02 ARI 3 May 2006 9:5

70. Vega RB, Huss JM, Kelly DP. 2000. Mol. Cell. Biol. 20:1868–7671. Akimoto T, Pohnert SC, Li P, Zhang M, Gumbs C, et al. 2005. J. Biol. Chem. 280:19587–

9372. Baar K, Wende AR, Jones TE, Marison M, Nolte LA, et al. 2002. FASEB J. 16:1879–8673. Pilegaard H, Saltin B, Neufer PD. 2003. J. Physiol. 546:851–5874. Terada S, Tabata I. 2004. Am. J. Physiol. Endocrinol. Metab. 286: E208–1675. Lin J, Wu H, Tarr PT, Zhang CY, Wu Z, et al. 2002. Nature 418:797–80176. Wang YX, Lee CH, Tiep S, Yu RT, Ham J, et al. 2003. Cell 113:159–7077. Grimaldi PA. 2003. Biochem. Soc. Trans. 31:1130–3278. Wang YX, Zhang CL, Yu RT, Cho HK, Nelson MC, et al. 2004. PLoS Biol. 2:e29479. Goodyear LJ, Chang PY, Sherwood DJ, Dufresne SD, Moller DE. 1996. Am. J. Physiol.

Endocrinol. Metab. 271:E403–880. Aronson D, Dufresne SD, Goodyear LJ. 1997. J. Biol. Chem. 272:25636–4081. Murgia M, Serrano AL, Calabria E, Pallafacchina G, Lomo T, Schiaffino S. 2000. Nat.

Cell Biol. 2:142–4782. Pallafacchina G, Calabria E, Serrano AL, Kalhovde JM, Schiaffino S. 2002. Proc. Natl.

Acad. Sci. USA 99:9213–1883. Rommel C, Bodine SC, Clarke BA, Rossman R, Nunez L, et al. 2001. Nat. Cell Biol.

3:1009–1384. Lai KM, Gonzalez M, Poueymirou WT, Kline WO, Na E, et al. 2004. Mol. Cell. Biol.

24:9295–30485. Chakkalakal JV, Stocksley MA, Harrison MA, Angus LM, Deschenes-Furry J, et al. 2003.

Proc. Natl. Acad. Sci. USA 100:7791–9686. Chakkalakal JV, Harrison MA, Carbonetto S, Chin E, Michel RN, et al. 2004. Hum. Mol.

Genet. 13:379–8887. Webster C, Silberstein L, Hays AP, Blau HM. 1988. Cell 52:503–1388. Shavlakadze T, White J, Hoh JF, Rosenthal N, Grounds MD. 2004. Mol. Ther. 10:829–4389. Krook A, Bjornholm M, Galuska D, Jiang XJ, Fahlman R, et al. 2000. Diabetes 49:284–9290. Ryder JW, Yang J, Galuska D, Rincon J, Bjornholm M, et al. 2000. Diabetes 49:647–5491. Hickey MS, Carey JO, Azevedo JL, Houmard JA, Pories WJ, et al. 1995. Am. J. Physiol.

Endocrinol. Metab. 268:E453–5792. Song XM, Ryder JW, Kawano Y, Chibalin AV, Krook A, Zierath JR. 1999. Am. J. Physiol.

Regul. Integr. Comp. Physiol. 277:R1690–9693. Henriksen EJ, Bourey RE, Rodnick KJ, Koranyi L, Permutt MA, Holloszy JO. 1990.

Am. J. Physiol. Endocrinol. Metab. 259:E593–9894. Ryder JW, Bassel-Duby R, Olson EN, Zierath JR. 2003. J. Biol. Chem. 278:44298–30495. Carling D. 2004. Trends Biochem. Sci. 29:18–2496. Merrill GF, Kurth EJ, Hardie DG, Winder WW. 1997. Am. J. Physiol. Endocrinol. Metab.

273:E1107–1297. Mu J, Brozinick JT Jr, Valladares O, Bucan M, Birnbaum MJ. 2001. Mol. Cell 7:1085–9498. Tanner CJ, Barakat HA, Dohm GL, Pories WJ, MacDonald KG, et al. 2002. Am. J.

Physiol. Endocrinol. Metab. 282:E1191–9699. Luquet S, Lopez-Soriano J, Holst D, Fredenrich A, Melki J, et al. 2003. FASEB J. 17:2299–

301100. Bodine SC, Latres E, Baumhueter S, Lai VK, Nunez L, et al. 2001. Science 294:1704–8101. Gomes MD, Lecker SH, Jagoe RT, Navon A, Goldberg AL. 2001. Proc. Natl. Acad. Sci.

USA 98:14440–45102. Stevenson EJ, Giresi PG, Koncarevic A, Kandarian SC. 2003. J. Physiol. 551:33–48


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u. R

ev. B

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006.

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. Dow

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ded

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07/0

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or p

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nly.

ANRV277-BI75-02 ARI 3 May 2006 9:5

103. Latres E, Amini AR, Amini AA, Griffiths J, Martin FJ, et al. 2005. J. Biol. Chem. 280:2737–44

104. Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, et al. 2004. Cell 117:399–412105. Guttridge DC, Mayo MW, Madrid LV, Wang CY, Baldwin AS Jr. 2000. Science 289:2363–

66106. Cai D, Frantz JD, Tawa NE Jr, Melendez PA, Oh BC, et al. 2004. Cell 119:285–98107. Zhu X, Yeadon JE, Burden SJ. 1994. Mol. Cell. Biol. 14:8051–57108. Wang XX, Blagden C, Fan JH, Nowak SJ, Taniuchi I, et al. 2005. Genes Dev. 19:1715–22109. O’Mahoney JV, Guven KL, Lin J, Joya JE, Robinson CS, et al. 1998. Mol. Cell. Biol.

18:6641–52110. Storer TW, Magliano L, Woodhouse L, Lee ML, Dzekov C, et al. 2003. J. Clin. En-

docrinol. Metab. 88:1478–85111. Sinha-Hikim I, Artaza J, Woodhouse L, Gonzalez-Cadavid N, Singh AB, et al. 2002. Am.

J. Physiol. Endocrinol. Metab. 283:E154–64112. Eriksson A, Kadi F, Malm C, Thornell LE. 2005. Histochem. Cell Biol. 124:167–75

RELATED REVIEWS

1. Lee SJ. 2004. Annu. Rev. Cell Dev. Biol. 20:61–862. Rennie MJ, Wackerhage H, Spangenburg EE, Booth FW. 2004. Annu. Rev. Physiol.

66:799–283. Pownall ME, Gustafsson MK, Emerson CP Jr. 2002. Annu. Rev. Cell Dev. Biol. 18:747–834. Clark KA, Mcelhinny AS, Beckerle MC, Gregorio CC. 2002. Annu. Rev. Cell Dev. Biol.

18:637–7065. Geeves MA, Holmes KC. 1999. Annu. Rev. Biochem. 68:687–728


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Contents ARI 22 April 2006 9:16

Annual Reviewof Biochemistry

Volume 75, 2006Contents

Wanderings of a DNA Enzymologist: From DNA Polymerase to ViralLatencyI. Robert Lehman � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 1

Signaling Pathways in Skeletal Muscle RemodelingRhonda Bassel-Duby and Eric N. Olson � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �19

Biosynthesis and Assembly of Capsular Polysaccharides inEscherichia coliChris Whitfield � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �39

Energy Converting NADH:Quinone Oxidoreductase (Complex I)Ulrich Brandt � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �69

Tyrphostins and Other Tyrosine Kinase InhibitorsAlexander Levitzki and Eyal Mishani � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �93

Break-Induced Replication and Recombinational Telomere Elongationin YeastMichael J. McEachern and James E. Haber � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 111

LKB1-Dependent Signaling PathwaysDario R. Alessi, Kei Sakamoto, and Jose R. Bayascas � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 137

Energy Transduction: Proton Transfer Through the RespiratoryComplexesJonathan P. Hosler, Shelagh Ferguson-Miller, and Denise A. Mills � � � � � � � � � � � � � � � � � � � � � � 165

The Death-Associated Protein Kinases: Structure, Function, andBeyondShani Bialik and Adi Kimchi � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 189

Mechanisms for Chromosome and Plasmid SegregationSantanu Kumar Ghosh, Sujata Hajra, Andrew Paek,

and Makkuni Jayaram � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 211

Chromatin Modifications by Methylation and Ubiquitination:Implications in the Regulation of Gene ExpressionAli Shilatifard � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 243

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Structure and Mechanism of the Hsp90 Molecular ChaperoneMachineryLaurence H. Pearl and Chrisostomos Prodromou � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 271

Biochemistry of Mammalian Peroxisomes RevisitedRonald J.A. Wanders and Hans R. Waterham � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 295

Protein Misfolding, Functional Amyloid, and Human DiseaseFabrizio Chiti and Christopher M. Dobson � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 333

Obesity-Related Derangements in Metabolic RegulationDeborah M. Muoio and Christopher B. Newgard � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 367

Cold-Adapted EnzymesKhawar Sohail Siddiqui and Ricardo Cavicchioli � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 403

The Biochemistry of SirtuinsAnthony A. Sauve, Cynthia Wolberger, Vern L. Schramm, and Jef D. Boeke � � � � � � � � � � � 435

Dynamic Filaments of the Bacterial CytoskeletonKatharine A. Michie and Jan Lowe � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 467

The Structure and Function of Telomerase Reverse TranscriptaseChantal Autexier and Neal F. Lue � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 493

Relating Protein Motion to CatalysisSharon Hammes-Schiffer and Stephen J. Benkovic � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 519

Animal Cytokinesis: From Parts List to MechanismsUlrike S. Eggert, Timothy J. Mitchison, and Christine M. Field � � � � � � � � � � � � � � � � � � � � � � � � 543

Mechanisms of Site-Specific RecombinationNigel D.F. Grindley, Katrine L. Whiteson, and Phoebe A. Rice � � � � � � � � � � � � � � � � � � � � � � � � � � 567

Axonal Transport and Alzheimer’s DiseaseGorazd B. Stokin and Lawrence S.B. Goldstein � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 607

Asparagine Synthetase ChemotherapyNigel G.J. Richards and Michael S. Kilberg � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 629

Domains, Motifs, and Scaffolds: The Role of Modular Interactions inthe Evolution and Wiring of Cell Signaling CircuitsRoby P. Bhattacharyya, Attila Remenyi, Brian J. Yeh, and Wendell A. Lim � � � � � � � � � � � � � 655

Ribonucleotide ReductasesPar Nordlund and Peter Reichard � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 681

Introduction to the Membrane Protein Reviews: The Interplay ofStructure, Dynamics, and Environment in Membrane ProteinFunctionJonathan N. Sachs and Donald M. Engelman � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 707

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Relations Between Structure and Function of the MitochondrialADP/ATP CarrierH. Nury, C. Dahout-Gonzalez, V. Trezeguet, G.J.M. Lauquin,G. Brandolin, and E. Pebay-Peyroula � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 713

G Protein–Coupled Receptor RhodopsinKrzysztof Palczewski � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 743

Transmembrane Traffic in the Cytochrome b6 f ComplexWilliam A. Cramer, Huamin Zhang, Jiusheng Yan, Genji Kurisu,

and Janet L. Smith � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 769

INDEXES

Subject Index � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 791

Author Index � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 825

ERRATA

An online log of corrections to Annual Review of Biochemistry chapters (if any, 1977 tothe present) may be found at http://biochem.annualreviews.org/errata.shtml

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signaling pathways in skeletal muscle remodeling

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