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doi: 10.1111/j.1365-2796.2010.02334.x

Can muscle regeneration fail in chronic inflammation: aweakness in inflammatory myopathies?

I. Loell & I. E. Lundberg

FromtheRheumatologyUnit,DepartmentofMedicine,KarolinskaUniversityHospital,Solna,Stockholm,Sweden

Abstract. Loell I, Lundberg IE (Karolinska UniversityHospital, Solna, Stockholm, Sweden) Can muscleregeneration fail in chronic inflammation: a weak-ness in inflammatory myopathies? (Review) J InternMed2010;doi:10.1111/j.1365-2796.2010.02334.x.

Idiopathic inflammatory myopathies (IIMs), collec-tively termed myositis, include three major sub-groups: polymyositis, dermatomyositis and inclu-sion body myositis. IIMs are characterized clinicallyby muscle weakness and reduced muscle endur-ance preferentially affecting the proximal skeletalmuscle. In typical cases, inflammatory cell infil-trates and proinflammatory cytokines, alarminsand eicosanoids are present in muscle tissue.Treatment with glucocorticoids and other immuno-suppressants results in improved performance,but complete recovery is rarely seen. The mecha-nisms that cause muscle weakness and reducedmuscle endurance are multi-factorial, and differentmechanisms predominate in different phases ofdisease. It is likely that a combination of immune-mediated and nonimmune-mediated mechanismscontributes to clinical muscle symptoms. Immune-

mediated mechanisms include immune cell-medi-ated muscle fibre necrosis as well as direct effectsof various cytokines on muscle fibre contractility.Among the nonimmune-mediated mechanisms, anacquired metabolic myopathy and so-called endo-plasmic reticulum stress may be important. Thereis also a possibility of defective repair mechanisms,with an influence of both disease-related factorsand glucocorticoid treatment. Several proinflamma-tory molecules observed in muscle tissue of myosi-tis patients, including interleukin (IL)-1, IL-15, tu-mour necrosis factor, high-mobility group box-1and eicosanoids, have a role in muscle fibre regen-eration, and blocking these molecule may impairmuscle repair and recovery. The delicate balancebetween immunosuppressive treatment to downre-gulate proinflammatory molecules and an inhibi-tory effect on muscle fibre regeneration needs to befurther understood. This would also be relevant forother chronic inflammatory diseases.

Keywords: cytokines, eicosanoids, inflammation,inflammatory myopathies, myositis, pathogenesis,physicalexercise, regeneration.

Background

Idiopathic inflammatory myopathies (IIMs), collec-tively known as myositis, are characterized clini-cally by muscle weakness and a low level of muscleendurance preferentially affecting the proximalskeletal muscle. Initial symptoms include difficultyin climbing stairs and rising from a chair. Muscleweakness may develop over weeks to months intosevere weakness, and occasionally, patients maybecome wheelchair dependent. Difficulty in swal-lowing or breathing may also occur owing toinvolvement of the pharyngeal or thoracic muscles.Pain is a less common problem and is usuallyreported as delayed onset muscle soreness afterexercise. A typical finding from muscle biopsies isinflammatory cell infiltrates composed mainly of T

cells, macrophages and dendritic cells [1, 2]. Basedon various clinical and histopathological pheno-types, three major subgroups of IIMs have beenidentified: polymyositis, dermatomyositis and inclu-sion body myositis (IBM) (Tables 1 and 2) (Fig. 1a–c)[3]. Other organs are frequently involved, such asskin in dermatomyositis and lung in both polymyo-sitis and dermatomyositis. Less often, the joints,heart and gastrointestinal tract are affected. Au-toantibodies are commonly found in IIMs, and posi-tive antinuclear autoantibodies are found in up to80% of cases of polymyositis and dermatomyositisbut less frequently in IBM (20%) (Table 1) [4]. Treat-ment is based on glucocorticoids in high doses overweeks to months, often in combination with otherimmunosuppressants such as azathioprine ormethotrexate [5].

ª 2011 The Association for the Publication of the Journal of Internal Medicine 1

Review |

Themolecularmechanisms that causemuscleweak-ness and reducedmuscle endurance in patients withmyositis have not been fully clarified. These mecha-nisms may vary between patients and in differentphases of the disease. It has been suggested that thecause ofmuscleweakness is loss ofmuscle fibres be-causeoffibredegeneration andnecrosis as a result ofdirect cytotoxic effects of T cells [6]. However, there isa dissociation between the degree of histopathologi-cal changes and the degree of muscle weakness,which suggests that othermechanismsmayalso leadto low muscle performance. One possibility is aneffect of cytokines, released from the infiltratinginflammatory cells, on muscle contractile propertiesincluding effects on Ca2+ release from the sarcoplas-mic reticulum as has been demonstrated for tumournecrosis factor (TNF) and more recently also for the

alarmin high-mobility group box (HMGB)1 [7, 8].Both TNF and HMGB1 have been detected inmuscletissue of myositis patients (Table 3) [9]. Anothermechanism that may contribute to the low muscleperformance is loss of capillaries in muscle tissueand, as a consequence, tissue hypoxia which couldhave a negative effect on muscle performance [10,11]. There are also signs of nonimmunemechanismsin muscle tissue of myositis patients, includingendoplasmic reticulum (ER) stress, that could affectmuscleperformance [12].

Most patients have a partial clinical improvementwith immunosuppressive treatment, but few recovertheir formermuscle performance. The reason for thisis unclear, butmay be owing to persistent inflamma-tion or merely inflammatory molecules that have a

Table 1 Presentationof clinical symptomsandautoantibodies insubsetsofmyositis

Clinical symptoms Polymyositis Dermatomyositis Inclusionbodymyositis (IBM)

Proximalmuscleweakness ++ ++ ++ (quadriceps)

Distalmuscleweakness + + ++ (fingerflexors)

Lowmuscleendurance ++ ++ +

Skinrash + (mechanic’shands) ++(heliotroperash,

Gottron’spapulesorsign)

)

Interstitial lungdisease (ILD) + + )

Nonerosivearthritis + + )

Heart involvement (myocarditis) + + )

Autoantibodies 80% 80% 20%

++:pronouncedsymptomspresent inmanypatients.+:present lessoftenormildsymptoms.

Table 2 Musclebiopsycharacteristics insubsetsofmyositis

Musclebiopsy feature Polymyositis Dermatomyositis Inclusionbodymyositis (IBM)

Inflammatorycell infiltrateswithpreferentially

endomysialdistribution

++ + ++

Inflammatorycell infiltrateswithpreferentially

aperimysialdistribution

+ ++ +

CD8+Tcells in infiltrates ++ ) ++

CD4+Tcells in infiltrates ++ ++ ++

Macrophages ++ ++ ++

Bcells ) + )

Plasmacytoiddendritic cells (pDCs) + ++ +

Majorhistocompatibilitycomplex (MHC)class I

expressiononmusclefibres

+ + +

Capillary loss + ++ ?

Perifascicular ‘atrophy’ofmusclefibres + ++ ?

I. Loell & I. E. Lundberg | Review: Muscle weakness in myositis

2 ª 2011 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine

negative effect onmuscle contractility, or apersistentatrophy because of disuse or defectivemuscle regen-eration. Another explanationcouldbe replacement ofmuscle tissue by fat which is often seen in patientswith IBM, regardless of immunosuppressive treat-ment. Possible molecular mechanisms that couldcontributeto thepersistentchronicmuscleweaknessin polymyositis and dermatomyositis will be furtherdiscussedbelow.

Muscle weakness in myositis

Loss of muscle fibres owing to myocytotoxic effect of immune cells

The most often advocated mechanism of muscleweakness inmyositis is an immune-mediated loss ofmuscle fibres through a myocytotoxic effect of infil-trating inflammatory cells [6]. Muscle tissue in poly-myositis, dermatomyositis and IBM is typically char-acterized by infiltration of inflammatory cells; inparticular, of T cells, macrophages, dendritic cellsand occasionally B cells [2, 13]. The T-cell infiltratesare composed of CD4+ and CD8+ T cells [2]. A directcytotoxic effect throughan interactionbetweenCD8+T cells andmajor histocompatiblility complex (MHC)class I onmuscle fibers has been suggested as a me-chanismformusclefiberdamage inpolymyositis andinclusionbodymyositis. However, the costimulatorymolecules required for the T cell-mediated cytotoxiceffects have not been convincingly demonstrated inmuscle tissue of myositis patients. In the light ofthis, the recently demonstrated high prevalence ofCD28null T cells inmuscle tissue of myositis patientsis of particular interest as these T cells have a pheno-type that resembles natural killer (NK) cells and canexert a cytotoxic effect without CD28 and its ligands[14]. It is also interesting that the NK cell propertiesare observed for both CD4+ and CD8+ CD28null Tcells. Therefore, T cell-mediatedmyocytotoxicity andloss of muscle fibres could be induced by both CD4+

and CD8+ CD28null T cells (Fig. 2), but whetherCD28null T cells really have a myocytotoic effect re-mains tobedetermined.

Cytokine-mediated muscle weakness

The presence of several cytokines and chemokineshas been reported in muscle tissue of myositis pa-tients. Cytokines have pleiotropic effects and mayhave pro- or anti-inflammatory properties and there-by serve as targets for therapy. Several differentcytokineshaveeffects onmuscle fibres, bothonmus-cle fibre contractility and remodelling; these effectswill be the focus of the discussion in this review. The

(a)

(b)

(c)

Fig. 1 (a–c) Characteristics of healthymuscle and ofmusclefrom patients with polymyositis and dermatomyositis. (a)Cross-sectional muscle biopsy tissue from a healthy subject(haematoxylinandeosinstaining). Image courtesyofDrCeci-lia Grundtman. (b) Cross-sectional muscle biopsy samplefrom a patient with polymyositis; image shows fibre sizevariation, several fibres with central nuclei, mononuclearinflammatory cells with an endomysial distribution and sur-rounding muscle fibres (haematoxylin and eosin staining),degenerating fibres (thick arrows) and regenerating fibres(broken arrows). Image courtesy of Dr Inger Nennesmo. (c)Cross-sectional muscle biopsy sample from a patient withdermatomyositis; image shows a perimysial and perivascu-lar inflammatory cell infiltrate and perifascicular distributionof small fibres (arrows) so-called perifascicular muscleatrophy). Often, these smaller fibres are regenerating fibres.ImagecourtesyofDr IngerNennesmo.


ª 2011 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine 3

cellular source of cytokines in muscle tissue may beinfiltrating inflammatory cells or other cellularsourcessuchasendothelial cellsormusclefibres (Ta-ble 3) (Fig. 2). Chemokines have a role in attractingcells into the tissue of inflammation, in this case intomuscle tissue, and are also possible targets of ther-apy, although their role in disease mechanisms ofmyositis has not been well documented and will notbe furtherdiscussed inthis review.

Tumour necrosis factor has a central role in severalchronic inflammatory diseases including rheuma-toid arthritis and Crohn’s disease [15]. It is also clearthatTNFhascataboliceffectsonmuscle in inflamma-tory conditions [16]. TNF issecretedbymacrophages,monocytes, T cells, NK cells and neutrophils [17] andcanbe releasedbydamagedmuscle fibresuponskel-etal muscle injury (Fig. 2) in inflammatory myopa-thies and Duchenne muscular dystrophy [18]. TNFhas several roles in inflammation including activa-tion and chemotaxis of leucocytes, expression ofadhesionmolecules and regulation of the secretion ofotherproinflammatorycytokines [17].

Tumour necrosis factor appears to be importantthroughout the degenerative phase of postinjurymuscle regeneration by several mechanisms [19,20]. TNF expression is upregulated in injured mus-cle fibres during the repair process and returns tonormal during the first days postinjury. [18]. TNFacts via promoting the activation of nuclear factorkappa-light-chain-enhancer of activated B cells(NFjB) which causes proteolysis and can also pro-mote the expression of atrogin-1, leading to muscleprotein catabolism [19, 20]. TNF expression in dam-aged muscle fibres does not correlate with the levelof inflammatory infiltrates in muscle tissue [21]thus suggesting that TNF in muscle fibres may haveother functions besides the conventional proinflam-matory properties. In primary myoblasts, it hasbeen shown that TNF is able to activate quiescentsatellite cells as well as enhance cell proliferationand promote differentiation (Fig. 2) [22]. This sug-gests that TNF has both degenerative and regenera-tive capacities within skeletal muscle. In addition,TNF has a direct negative effect on muscle fibre con-tractility through an inhibitory effect on Ca2+ release

Table 3 Molecular elements (cytokines, chemokines and lipid mediators) of the immune response detected in muscle tissue of

myositispatients

Cytokines Origin

TNF Scatteredmononuclearcells,macrophagecytoplasm,degenerating

andregeneratingmusclefibrenuclei, endomysial andperimysial connective tissue

IFN-a Plasmacytoiddendriticcells

IFN-c Tcells

IL-1 Inflammatorycells, endothelial cells, capillaries

IL-6 Sparseexpression inscattered inflammatorycells

IL-15 Mononuclear inflammatorycells,predominantlymacrophages

IL-18 Endomysialandperimysialmacrophagesanddendriticcells

HMGB-1 Macrophages,endothelial cells,musclefibres

Chemokines

CXCL9 Mononuclear inflammatorycells, somemyofibres

CXCL10 Tcellsandmacrophages

CCL2 Bloodvessels,Tcells

CCL3 Mononuclear inflammatorycells,myofibres

CCL19 Myofibres

Lipidmediators

mPGES-1 (PGE2) Macrophages

5-LO(LTB4) Macrophages

TNF, tumour necrosis factor; IFN, interferon; IL, interleukin; HMGB-1, high-mobility group box-1; CXCL, a-chemokine induc-ible by IFN-c; CCL, b-chemokine effecting leucocyte activation and trafficking with role in tissue repair and skeletal muscleregeneration;mPGES-1,microsomalprostaglandinEsynthase1;5-LO,5 lipoxygenase;LTB4, leukotrieneB4.



from the sarcoplasmic reticulum thus causing mus-cle fatigue [7].

Within muscle tissue from patients with myositis,TNF is mainly expressed by scattered mononuclearcells [23]. However, the role of TNF in the pathogene-sis of myositis is still unclear, as treatment with TNFblockade has led to conflicting results and evencausedworseningof inflammation [24].

Interleukin-1a and -1b are among the most consis-tently expressed cytokines inmuscle tissue ofmyosi-tispatients,andIL-1receptorsareexpressedonmus-cle fibres (Table 3) [25]. IL-1 may induce TNF, andboth IL-1b andTNFmay inhibit expressionandactiv-ity of growth hormone and insulin-like growth factor1 in muscle fibres (Fig. 2). In an open study usingtreatment with IL-1 blockade (anakinra), seven of 15patients showed improvements in a number of clini-calparameters includingmuscleperformance,whichmight indicate a role of IL-1 inmuscleperformance inmyositis (unpublisheddata).

Interleukin-6 is a pleiotropic cytokine that regulatesimmune response, inflammation and haematopoie-sis. IL-6 is produced by macrophages, fibroblasts,endothelial cells andT cells and is rapidly inducedbymultiple stimuli such as viral infection, lipopolysac-charide andother cytokines [26]. There are a numberof autoimmune and inflammatory diseases in whichIL-6 is pathologically overproduced, and blockade ofthiscytokinesignallingpathway isapprovedfor treat-ment of rheumatoid arthritis [27]. However, datahave shown that IL-6mayalso exert inhibitory effectson TNF and IL-1 production (Fig. 2) [28]. Stimulationof IL-1 receptor antagonist (IL-1ra) and IL-10hasalsobeen suggested as one of the anti-inflammatory ef-fectsof IL-6 [29].

Interleukin-6 also has a dual effect on skeletalmuscle. Overexpression of IL-6 leads to skeletalmuscle atrophy in mice accompanied by an in-creased expression of ubiquitins and cathepsins,which was blocked by treatment with a muscleIL-6 receptor antibody [30]. Local infusion of IL-6

Dendri c cellsT cellsMuscle cellsCD68+ CD163+CD4+/CD8+

Endothelial cellsNeutrophils Macrophages

IL-6, IL-15,

Cytotoxic

TNF, HMGB1PGs, LTB4

IFNLTB4 IFN

IL-1α, IL-6IL-15?HMGB1, LTB4TNF, IL-6

LTB4

IL-15

IFNTNF

CD28null

M bl

Quicsence Ac va on Prolifera on Differen a on Fusion

Myoblasts

MyocytesResidual SC pool

Muscle Damage

MyoD+Myogenin+MRF4

Pax7+Myf5+MyoD+

Pax7+Myf5+

Protein accumula on

Pax7+

ER stress

Fig. 2 A schematic diagram illustrating the positive effects onmuscle fibre regenerationand remodelling ofmolecules thatmighthaveadual role inmuscle tissuebothpromoting inflammationandaffectingskeletalmusclefibre regenerationand remodelling inmyositis patients. The key molecules can influence each other (red arrows) as well as the different phases of skeletal muscleregeneration; the focus in thisdiagram ison the less frequentlydescribedpositiveeffects (bluearrows) rather thantheestablishednegativeeffects.Thebrokenbluearrowindicates inhibitingeffectsonmusclefibredifferentiation.Uponskeletalmusclefibredam-age, an inflammatory ⁄ immune responseprecedesmyogenesis. The local immune response inmuscle tissuehasadirect effect onsatellite cell activation,proliferation,differentiationor fusion.This local immuneresponsemightbe disturbed (e.g. by immunosup-pressive treatment), thus potentially influencing the functional restoration of fibres injured in variousways. Therefore, suppress-ing the immunesystemorblockingsingle cytokinesor receptorsmightdisturbskeletalmuscle regeneration.SC,satellite cells.



decreased myofibrillar protein without entering theblood stream or the neighbouring muscle [31]. Inhumans, IL-6 has in recent years been identifiedas a ‘myokine’, a cytokine produced and secretedby skeletal muscle, and it has been demonstratedthat plasma concentrations of IL-6 as well as IL-6mRNA and protein expression in muscle tissue areelevated during physical exercise. These increasedlevels are related to exercise duration and inten-sity, the muscle mass involved as well as endur-ance capacity [32]. Exercise has also been found toincrease the production of IL-6 receptors in humanmuscle thus suggesting a postexercise sensitizingmechanism [33].

The exact role of IL-6 in skeletal muscle in relationto exercise is still unclear, but recent work hasidentified this cytokine as an essential regulatorof satellite cell-mediated overload-induced musclehypertrophy suggesting a role in muscle remodel-ling [34]. In an experimental approach, IL-6) ⁄ ) miceshowed hypertrophy during overload but accompa-nied by a large increase in noncontractile tissue,implying that IL-6 is a critical factor in the regula-tion of the fibrotic response of skeletal muscle dur-ing overload-induced hypertrophy [35]. Blockingthe effect of IL-6 produces unwanted effects on met-abolic homeostasis such as an increase in wholebody weight, total cholesterol and glucose intoler-ance, which might point towards a negative role inskeletal muscle [36].

In patients with dermatomyositis, elevated serumlevels of IL-6 correlated with disease activity [37];however, only low levels of IL-6 gene expression weredetected inmuscle tissue frommyositispatients, andIL-6protein expressionwasonlyobserved inaminor-ity of the inflammatory cells in a fraction of patients(Table 3) [23]. Therefore, the role of IL-6 in the devel-opment of muscle weakness in myositis is unclear,and a potential negative effect onmusclemetabolismand muscle fibre regeneration should be taken intoaccount if treatment with IL-6 blockade is consid-ered.

Interleukin-15 is another cytokine that has effectsbothonthe immunesystemandonskeletalmusclefi-bres and that may have a role in the pathogenesis ofmyositis. This cytokine with proinflammatory prop-erties is expressed in macrophages and endothelialcells inducing chemotaxis and proliferation of T cells(Table 3). IL-15 may also contribute to an increasedproduction of other proinflammatory cytokines suchas TNF, interferon (IFN)-c and IL-17 in T cells [38]. In

polymyositis and dermatomyositis, IL-15 and itsreceptor IL-15Ra have been observed in muscle tis-sue, and, of interest, IL-15 was still expressed aftermore than 6 months of immunosuppressive treat-ment in patients with persistent muscle weakness[39] (ZongM,unpublisheddata).

Withinskeletalmusclefibres, IL-15canstimulatedif-ferentiated myocytes and muscle fibres to accumu-late contractile proteins, and IL-15 can induce anaccumulationofmyosinheavychainprotein indiffer-entiated myotubes in culture (Fig. 2) [40]. Anothermechanism involved in the anabolic effects of IL-15on skeletalmuscle is a decrease in the rate of proteol-ysis [41], which is independent of changes in the lev-els of hormones such as insulin or glucocorticoids[42]. IL-15 mRNA expression in skeletal muscle hasbeen shown to dominate in type II (glycolytic) musclefibres [43]. IL-15 is also important in angiogenesiswhich might be the main reason for the changes inplasma levels of this cytokine after acute exercise[44]. The roleof IL-15 in inflammationandthecontra-dictory role in preventing muscle wasting raise thequestion of what therapeutic approach to take withIL-15overexpression.

High-mobility group box 1 is a highly conserved,ubiquitously expressed nonhistone DNA-bindingprotein that upon secretion serves as an alarmin,activating the immune system, but also causesmus-cle regeneration and repair. HMGB1 can be translo-cated from the nucleus of necrotic cells, but can alsobe actively released by monocytes and macrophages[45]. Extracellular expressionofHMGB1hasbeenre-ported inmuscle tissue of patients with polymyositisor dermatomyositis as well as extranuclear expres-sion in infiltrating mononuclear cells, endothelialcells and skeletal muscle (Table 3) [46]. After treat-mentwithhighdosesof glucocorticoids formore than3 months, the total HMGB1 protein expression wasdownregulated, but cytoplasmic expression re-mained abnormal in muscle fibres and endothelialcells in patients with persistent muscle weaknesssuggesting a potential role in chronic weakness inmyositis patients. HMGB1 has the potential toupregulate MHC class I expression (Fig. 2) in musclefibres; this upregulation is not normally seen andis believed to be involved in IIM pathogenesis. Inphysiological experiments, HMGB1 exposure irre-versibly impaired Ca2+ release during repeatedtetanic stimulation [8], which is accompanied by areduced force production; thus, HMGB1 mightcontribute to the muscle fatigue that characterizesmyositis.



Results of recent studies have demonstrated thatHMGB1canmodulate stemcell function and therebytissue regeneration. HMGB1 has skeletal muscleregenerative capability as evidenced by enhancedmyoblast recruitment to the site of injury and in-creased numbers of regenerating fibres as well asblood vessel formation in amousemodel of hindlimbischaemia (Fig. 2) [47]. Another potential regenera-tionmechanism of HMGB1was shown by promotionof differentiation of myogenic cells in a rat cell line[48, 49]. HMGB1 may therefore have both negativeand positive effects onmuscle fibres inmyositis. It isa potential target for new therapies, but its effects onmuscleperformancestill needtobeclarified.

Eicosanoids in myositis

Eicosanoids are signalling molecules generated byoxidation of 20-carbon fatty acids that exert complexcontrol over many systems and processes includinginflammationand immunity. There are different fam-ilies of eicosanoids, but only prostaglandins (PGs)and leukotrieneswillbediscussedhere.

Prostaglandins are a group of lipidmediators formedin response to various stimuli. They include PGD2,PGE2,PGF2aandPGI2 (prostacyclin) andare releasedoutside cells immediately after synthesis via cycloox-ygenase (COX) enzymes and terminal synthases.Theyexert theiractionsbybinding to receptorsonthetarget cells. PGswere initially considered to be proin-flammatory, as they could reproduce the cardinalsigns of inflammation; however, it is now clear thattheyalsopossessanti-inflammatoryactivity [50].

Human skeletal muscles have a considerable capac-ity to produce PGE2, PGD2, PGF2a and PGI2 [51].During muscle regeneration, myofibres as well asinfiltrating leucocytes secrete PGs that may influ-ence myogenesis (Fig. 2) [52]. PGE2 appears to be in-volved in a number of biological processes, includingprotein turnover and myogenesis, and is a potentmediator of muscular pain and inflammation [53–57]. IL-1b and TNF, which are highly expressed inmyositis muscle tissue, stimulate PGE2 productionin skeletalmuscles [9, 58–60]. Thisproductionmightbe the result of the enhanced expression of the termi-nal synthase microsomal PGE synthase-1 (mPGES-1) inmuscle tissue of patients withmyositis (Table 3)(Fig. 3). Moreover, this expression was not affectedby conventional immunosuppressive treatment.PGF2a is produced by myoblasts and can preventapoptosis as well as promote cell fusion (Fig. 2) [55].Similarly, in mice, PGI2 signalling controls myoblast

motility and enhances cell fusion [61], but whetherPGF2a and PGI2 are produced in muscle of myositispatients is not known. In mice, muscle injury in-duces secretionof PGE2, PGI2 andPGF2abyactivatedmyoblasts [62]. Simultaneously, invading leucocytesare capable of producing PGE2, yet little is knownabout the effect on myogenesis of PGs released fromleucocytes.

Leukotrienes are lipid mediators derived from mem-brane-released arachidonic acid. LTB4 is a powerfulchemoattractant to direct myeloid leucocytes andactivated T cells into inflamed tissue (Table 3) [63].LTB4 also shows involvement in the differentiation ofnaı̈ve T cells [64] as well as the ability to augment thecytokine production by activated T cells [65]. LTB4 isformedby the5-lipoxygenase (5-LO)pathwayandex-erts its actions mainly through the inducible, high-affinity leukotriene B4 receptor (BLT1) that is ex-pressed on neutrophils, eosinophils, macrophagesand, to a lesser extent, on T lymphocytes [66–70].BLT1 expression has been demonstrated in humanendothelial cells and smooth muscle cells [71]. Inaddition, LTB4 contributes tomuscle regenerationbypromotingproliferationanddifferentiationof satellitecells (Fig. 2) and differentiation of rat myoblaststhrough BLT1 receptors [64]. LTB4 production byhuman skeletal muscle has been determined bymicrodialysis and is upregulated in patients withfibromyalgia [56, 72]. In addition, enhancedexpression of 5-LOmRNA has been demonstrated inmuscle tissue from patients with polymyositis and

Fig. 3 Infiltrating inflammatory cells in muscle tissue of anuntreated patient with myositis; brown staining indicatesexpressionofmicrosomalprostaglandinEsynthase-1.



dermatomyositis, suggesting a role of 5-LO in thepathogenesisof thesediseases [73].

The transcription factor NFjB in muscle repair

When highlighting molecules that share their effectsbetween the immune system andmuscle fibre regen-eration andmuscle remodelling, thewell-establishedtranscription factor NFjB is of particular interest.NFjB is critical in immune reactions but also has arole in myogenesis, muscle regeneration andmuscleatrophy. Several of the cytokines discussedabove actthrough NFjB. This transcription factor is ubiqui-tously expressed, and its signalling pathway regu-lates cellular functions such as proliferation, differ-entiation, survival, apoptosis and the immuneresponse [74]. NFjB is composed of different subun-its responsible for the so-called classical or alterna-tive NFjB signalling pathways [75]. It has been re-ported that activation of NFjB family members isassociated with regulating myogenesis and muscleregeneration, and this involvement may be subunitspecificandoccursviaboth theclassical andalterna-tivepathways. Indegenerativemusclediseases,mus-cle fibres undergo a programme of regenerationwhich is the same as after muscle injury, and theNFjB pathway has been found to modulate thisregenerative process [76]. The effects ofNFjBseem tobe a balance between those of the classical and alter-native pathways. The classical signalling maintainsmyoblasts in the proliferative stage, preventing theirpremature differentiation, and once myogenic differ-entiation is initiated, this pathway is shut down. Thealternative pathway is then activated, promotingmitochondrial biogenesis, possibly to provide theforming myotubes with the required energy (Fig. 2[77]. Myogenic differentiation can be inhibited byNFjB throughstimulation of cyclinD1accumulationand cell cycle progression [78]. Another mechanismthrough which NFjB could inhibit myogenesis isthought tobe through the increasedexpressionof thetranscription factor Yin Yang1 which directly re-presses the synthesis of the differentiation genes a-actin, muscle creatine kinase and myosin heavychain IIb [79].

Nuclear factor kappa B regulates the expression ofproinflammatory cytokines, including IL-1b, IL-6, IL-15 and TNF, in systemic inflammatory disorderssuch as Duchenne muscular dystrophy, IIMs andrheumatoid arthritis [80, 81]. These cytokines arealso potent activators of NFjB, creating a positivefeedback loop [82]. IL-1b andTNFmaybothblock thedifferentiation of cultured myoblasts into myotubes

through the activation of NFjB [83]. Another mecha-nism ofmyogenic inhibition is through the reductionof cellular levels of MyoD protein by post-transcrip-tional modification. On NFjB activation, proinflam-matory cytokines can destabilize MyoD mRNA inskeletal muscle cells and thereby inhibit the transi-tion fromproliferationtodifferentiation [84].

In inflammatorymyopathies, NFjBactivation occursboth in infiltrating inflammatory cells and in musclefibres within themuscle tissue. Patients with inflam-matory myopathies have an overexpression of MHCclass I in muscle cells which is thought to induce ERstress,which in turn canactivateNFjB.Uponactiva-tion,NFjBregulates theexpressionofgenes inducingMHC class I causing a positive feedback for the pro-gressionof inflammatorymyopathies [12,23].

Nuclear factor kappa B cells can also induce expres-sion of proteins of the ubiquitin–proteasome systeminvolved in skeletal muscle protein degradation, andthis partly works through increased expression ofmuscle RING finger protein 1 (MuRF1). Increasedexpression of MuRF1 has been reported in animalmodelsofmuscleatrophyinducedbyimmobilization,IL-1andglucocorticoids [20].

Targeting NFjB for pharmacological therapy is anattractive option for chronic inflammatory diseasessuch as IIM. The NFjB pharmacological modelsavailable today involve curcumin [85], NBD peptide(NBD = NEMO binding domain where NEMO is in-cluded in aNFjB subunit essential for classic signal-ling) [86, 87] and L-arginine [88], [89] which protectthemuscleandstimulatemuscle regeneration.Asys-temic administration of NBDpeptide would probablyaffect the homeostatic functions of NFjB in immunesystem. Targeting NFjB in immune cells directly aswell as the muscle cells might give a more specificeffect. Another approach would be to target musclewasting-related alternatives downstream of NFjB,e.g. MuRF1, in order to inhibit muscle protein break-down.

Muscle weakness: an acquired metabolic myopathy

The main clinical symptom experienced by patientswith polymyositis and dermatomyositis is impairedendurance. Muscle endurance is dependent on oxi-dative type I fibres and requires an oxygen supply.Loss of capillaries in muscle tissue is a hallmark ofdermatomyositis. A reduced number of capillariescompared with the number in healthy individualshas been demonstrated in both the early and late



phases of polymyositis without detectable inflam-matory infiltrates suggesting an impaired micro-circulation in muscle in both polymyositis anddermatomyositis [10, 11]. Notably, several of thecytokines reported to have aberrant expression inmuscle tissue can be induced by hypoxia, includingTNF, IL-1 and the alarmin HMGB1. Further supportfor the role of hypoxia in skeletal muscle weaknessis the low levels of adenosine triphosphate andphosphocreatine recorded by magnetic resonancespectroscopy [90], as well as a decreased proportionof oxidative, type I muscle fibres in patients withestablished polymyositis or dermatomyositis andpersistent reduced muscle performance [91]. Theseobservations all support the notion of an acquiredmetabolicmyopathycausingmuscle fatigue.

Nonimmune mechanisms

MHC class I upregulation

An obvious finding in muscle biopsies from patientswith inflammatorymyopathies isMHCclass I expres-sioninmusclefibres,which isnotobserved inhealthyindividuals. Thismay be the only sign of pathology inmuscle tissue and may be present without adjacentinflammatory cell infiltrates. MHC class I can be in-duced by proinflammatory cytokines (e.g. IFNs, IL-1andHMGB1) that have been detected inmyositis tis-sue (Fig. 2). It is interesting that genetically modifiedmicewithmuscle-specificupregulationofMHCclass Ideveloped muscle weakness before inflammatoryinfiltrates could be detected in muscle tissue, sup-porting the notion that this phenotypic modificationofmuscle fibres couldaffectmuscle contractility [92].MHC class I expression could also be induced andsustained by the ER stress response (Fig. 2). This is aprotective mechanism in cells subjected to stress.Signs of ER stress have been observed in muscle tis-sue from both MHC class I transgenic mice and frompatientswithmyositis [12].

Major histocompatibility complex class I moleculesare localized in the ER and could thereby affect pro-tein synthesis of muscle fibres andmuscle fibre con-tractility. In single fibres fromMHCclass I transgenicmice, force production was reduced in slow twitchtype I fibresowing toanasyetundetermined intrinsiceffect [93]. A differential effect on fibre types resem-bles theclinicaleffect inmyositis, aspatientsmoreof-ten complain of reduced muscle endurance, whichmainly depends on oxidative type I muscle fibres,rather than impaired single high-force movements[94]. These data support the hypothesis that MHC

class I expression in muscle fibres could affect mus-cle performance, even in the absence of muscle fibrenecrosis or inflammatory cell infiltrates, and contrib-ute tochronicmuscle fatigue inmyositis.

Skeletal muscle regeneration

Another possible cause of the chronic persistentmuscle weakness observed in the three types ofmyo-sitis could be a defective repair mechanism after theloss of muscle fibres. The regeneration of skeletalmuscle depends on the balance between pro- andanti-inflammatory factors that determine whetherthe damage will be repaired with muscle fibrereplacement and functional contractility or with scartissue formation [95]. Muscle tissue has an inbornrepair mechanism whereby muscle fibres can regen-erate from satellite cells. Skeletal muscle regenera-tion includes three distinct stages, degeneration,muscle repair and remodelling, and follows a fairlyconsistent pattern irrespective of the underlyingcause of injury (e.g. direct trauma, tissue ischaemia,old age or genetic defects) [96, 97]. If the muscle re-pair mechanisms are inadequate, the consequencemight be reduced muscle function andmuscle wast-ing [97]. Adult skeletal muscle is a stable tissue withlimited nuclear turnover [98], but it has the ability torapidly regenerate in response to damage to main-tain well-innervated, vascularized and contractilemuscle. The well-orchestrated course of satellite cellactivation and differentiation is largely similar to thegene expression during embryonic development ofmuscle while the main difference is the presence ofimmunecells duringmuscle regeneration inmyositispatients [99]. Signs of fibre degeneration and regen-eration are classical histopathological features ofmyositis, but to what extent, the inflammatory re-sponse inmyositis is a feature that promotes muscleinjury or muscle growth, and repair is still inade-quatelyunderstood.

The initial event in thedegenerationofmuscle, necro-sis of muscle fibres, is triggered by disruption of thesarcolemma followed by increased serum levels ofproteins such as creatine kinase andmyoglobin [76].In the early phase of muscle damage, the injuredmuscle activates an inflammatory response drivenby T helper (Th)1 cytokines, such as IFNc and TNF.Neutrophils are rapid responders within the firsthours, followed by CD68-expressing M1 phenotypemacrophages during the first 24 h. These two celltypes contribute to further muscle membrane lysisby production of free radicals but also clear the cellu-lar debris by phagocytic removal [100]. Whether this



elimination of debris is of importance for furtherregeneration isnot fullyunderstood.

After the proinflammatory phase, quiescent Pax7-expressing muscle satellite cells are exposed to sig-nals such as IGF-1, fibroblast growth factor 2, andhepatocyte growth factor promoting activation, pro-liferation and migration to the site of injury (Fig. 1)[101]. During this stage, the cells becomeMyoD- andMyf5-expressing myoblasts. Throughout the shiftfrom the proliferative stage to the differentiationphase, theM1macrophages are replaced by CD163+

M2macrophages,activatedbyTh2cytokinessuchasIL-4, IL-10and IL-13. TheM2macrophages display amore anti-inflammatory phenotype and are foundduring the healing phase of acute inflammation, inwound-healing tissue and in chronic inflammation,but are rarely observed in myositis [100]. Followingthe proliferation stage, expression of myogenin andmyogenic regulatory factor 4 is upregulated, and themyoblasts become terminally differentiated and exitthe cell cycle. Thesemuscleprogenitor cells then fusetogetherorwith theexistingfibres to replace thedam-agedmuscle cells [76]. At present, it is not possible todistinguish the features of the chronic inflammatoryresponse in autoimmune myositis that cause injuryfrom those that promotemuscle regeneration and re-pair.

Effect of anti-inflammatory agents on muscle regeneration

Glucocorticoids in high doses still form the basis fortreatment of polymyositis and dermatomyositisalthough catabolic effects and steroid-induced mus-cle atrophy arewell-known side effects. The degree ofthese side effects in polymyositis and dermatomyosi-tis isuncertain, as thefibreatrophyhas recentlybeenquestioned [102–104]. Glucocorticoid-induced atro-phy is characterized by a decrease in muscle fibrecross-sectional area in fast twitch, type II muscle fi-bres with an accompanied decrease in musclestrength [105].Theactionsofglucocorticoidsonskel-etal muscle include both an inhibitory effect on pro-teinsynthesisandastimulatory effectonmusclepro-teolysis. The anti-anabolic outcome is a consequenceof both the inhibition of amino acid transport into themuscle [106] and the inhibition of IGF-1, a growthfactor that increases myogenesis but also decreasesproteolysis and apoptosis [107]. Glucocorticoids alsoactivatedifferentsystemsresponsible forproteindeg-radation (ubiquitin–proteasome system, cathepsinsand calpains) and stimulate muscle production ofmyostatin, a growth factor that downregulates satel-lite cell proliferation anddifferentiation [108].Muscle

wasting is illustrated by decreased levels of the tran-scription factor formuscle differentiation,MyoD, andit appears that glucocorticoids can stimulate the deg-radationofMyoD,at least in thenucleus.The levelsofanother myogenic transcription factor, myogenin,also seem to be reduced in response to dexametha-sone administration in murine C2C12 muscle cells[109]. Glucocorticoids also have an effect on theCOX-dependent PG synthetic pathway, downregu-lating cytosolic phospholipase A2, and thereforemight impair the role of PGE2 inmuscle regeneration[110, 111]. Thus, glucocorticoids may act as a dou-ble-edged sword in the recovery of strength inmyosi-tispatientsbyreducing inflammationbutat thesametime inhibiting muscle regeneration. This supportsthe need for more targeted therapies in these condi-tions.

Nonsteroidal anti-inflammatory drugs (NSAIDS) arepopular over the counter medications for treatingmuscle injury. They mainly inhibit COX enzymes inthe PG biosynthetic pathway [112]. It has beenshown that NSAIDs attenuate the exercise-inducedincrease in satellite cell number, supporting a rolefor PGs in muscle regeneration [113]. Furthermore,selective COX-2 inhibition results in decreasedproliferation of satellite cells, whereas nonselectiveCOX inhibition may decrease satellite cell differenti-ation and fusion [114]. Not only can COX inhibitorsaffect the satellite cell response to exercise, it ap-pears that the COX-2 pathway regulates muscleprotein synthesis and growth via several mecha-nisms that can be attenuated by COX-2 inhibition[115]. Traditional NSAIDs such as aspirin and ibu-profen are able to reduce the effects of PGs on skele-tal muscle regeneration.

Effects of exercise in inflammatory myopathies

Persistent muscle weakness and reduced muscleendurance could also be a consequence of a low levelof physical activity, as, until recently, myositis pa-tients were advised to refrain from exercise owing tofear of worsening muscle inflammation. However,several studies have demonstrated that physicalexercise, in combination with pharmacotherapy, issafe and improvesmuscle strengthandperformance,oxygen capacity and quality of life [91, 116–120]. It isinteresting thatphysical exercisewasfoundto induceashift infibre typecomposition towardsanormaldis-tribution, suggesting that exercise might have nor-malized oxygen tensionwithin themuscle tissue [91].Furthermore, exercise with creatine supplementa-tion led toahigher functional performance compared



with exercise alone [121]. Of note, 7 weeks of resis-tance exercise induced downregulation of genes thatregulate inflammation in muscle tissue suggestingthat exercise might reduce inflammation [122]. Ananti-inflammatory effect of training has also beenseen inhealthy individualsmeasuredas lower serumlevelsof IL-6andC-reactiveprotein [123].

Anti-inflammatory properties of physical exercisecould arise from the muscle cells themselves viasecretion of contraction-induced ‘myokines’, and, asmentioned above, both IL-6 and IL-15 appear tohave beneficial roles when released from muscle fi-bres. IL-6 is the first cytokine to be released into thecirculation upon initiation of exercise followed by arise in circulating levels of IL-1ra, IL-10 and solubletumour necrosis factor-receptor (sTNF-R), resultingin an anti-inflammatory environment [124]. Theanti-inflammatory properties of exercise-inducedIL-6 seem to have mainly systemic metabolic effects.Lower levels of TNF have been demonstrated inmuscle tissue after physical exercise in patientswith chronic heart failure [125] and exerciseresulted in decreased levels of TNF and increasedIL-10 within skeletal muscle with a fibre type spe-cific pattern in rats [126]. Exercise and muscle con-tractions might stimulate NFjB activation throughseveral pathways. The functions of exercise-stimu-lated NFjB are currently unknown, but it is possiblethat NFjBmay counteract oxidative stress, induce abrief proinflammatory response critical for muscleregeneration and lead to changes in postexercisemuscle glucose transport, glycogen repletion andlipid oxidation [127].

Inresponse tomuscleoverload,satellite cells areacti-vated and progress either to contribute to myotubefusion or to the pool of self-renewing satellite cells.Upon physical exercise, the release of inflammatorysubstances and ⁄or growth factors signal to the satel-lite cells thus regulating their activation and prolifer-ation. Aerobic exercise can induce satellite cell prolif-eration, and exercise-induced hypoxia may triggersystemic stem cell mobilization, which inmuscle tis-suewould be the satellite cell, that could be recruitedin muscle regeneration. Aerobic exercise may alsostimulate vascular endothelial growth factor secre-tion contributing to satellite cell proliferation andmigration. Whether these mechanisms are applica-ble to myositis patients still needs to be determined.Exercise has the potential to counteract the cataboliceffect of glucocorticoids on muscles, and this pro-vides further support for prescribing exercise as partof treatment formyositispatients.

Conclusions

The interplay between the immune system andmus-cle is complex and involves several mechanisms thatmay contribute tomuscle weakness and that need tobe taken into consideration when treating patientswith myositis. Different mechanisms may predomi-nate in different phases of disease (e.g. in early orestablished disease), and careful phenotyping of pa-tients is essential in future studies. Several of thecytokines, alarmins and eicosanoids that predomi-nate in muscle tissue may act both as catabolic andanabolic factors. The dual effect of these molecules –proinflammatory and anabolic ⁄catabolic – may alsobe relevant for other chronic inflammatory diseasesandshouldbethe focusof future research.

Conflict of interest statement

Noconflict of interestwasdeclared.

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Correspondence: Ingrid E. Lundberg MD, PhD, Rheumatology Unit,

Karolinska University Hospital, Solna, SE-171 76 Stockholm,

Sweden.

(fax:+46 8 5177 3080; e-mail: [email protected]).



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