Hindawi Publishing Corporation International Journal of Endocrinology Volume 2014, Article ID 309570, 11 pages http://dx.doi.org/10.1155/2014/309570 Review Article Intermuscular Fat: A Review of the Consequences and Causes OdessaAddison,1,2RobinL.Marcus,3,4PaulC.LaStayo,3,4,5andAliceS.Ryan1,2 1DivisionofGerontologyandGeriatricMedicine,DepartmentofMedicine,UniversityofMarylandSchoolofMedicine, 10NorthGreenStreet,BT/18/GRECC,Baltimore,MD21201,USA 2GeriatricResearch,EducationandClinicalCenter,BaltimoreVeteransAffairsMedicalCenter,Baltimore,MD21201,USA 3DepartmentofPhysicalTherapy,UniversityofUtah,SaltLakeCity,UT84108,USA 4DepartmentofExerciseandSportScience,UniversityofUtah,SaltLakeCity,UT84112,USA 5DepartmentofOrthopedics,UniversityofUtah,SaltLakeCity,UT84108,USA CorrespondenceshouldbeaddressedtoOdessaAddison;[email protected] Received24September2013;Accepted18December2013;Published8January2014 AcademicEditor:NicolaNapoli Copyright©2014OdessaAddisonetal.ThisisanopenaccessarticledistributedundertheCreativeCommonsAttributionLicense, whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited. Muscle’sstructuralcompositionisanimportantfactorunderlyingmusclestrengthandphysicalfunctioninolderadults.There isanincreasingamountofresearchtosupportthecleardisassociationbetweenthelossofmuscleleantissuemassandstrength withaging.Thisdisassociationimpliesthatfactorsinadditiontoleanmusclemassareresponsibleforthedecreasesinstrength andfunctionseenwithaging.Intermuscularadiposetissue(IMAT)isasignificantpredictorofbothmusclefunctionandmobility functioninolderadultsandacrossawidevarietyofcomorbidconditionssuchasstroke,spinalcordinjury,diabetes,andCOPD. IMATisalsoimplicatedinmetabolicdysfunctionsuchasinsulinresistance.Thepurposeofthisnarrativereviewistoprovidea reviewoftheimplicationsofincreasedIMATlevelsinmetabolic,muscle,andmobilityfunction.Potentialtreatmentoptionsto mitigateincreasinglevelsofIMATwillalsobediscussed. 1.Introduction Adipose tissue stored in subcutaneous depots, particularly in the gluteal-femoral region, is a negative predictor of The unique ability of adipose tissue to expand throughout metabolic syndrome and is cardioprotective [4–7, 15, 16]. lifeandreleaseahostofchemicalmessengersmakesadipose However, adipose tissue stored in ectopic locations outside not only a distinctive tissue but also the largest endocrine of the subcutaneous tissue such as in the muscle, liver, and organ in the body [1]. In the last twenty years, a rapid abdominalcavityislinkedwithchronicinflammation[10,17– expansion of our understanding of this unique organ has 19],impairedglucosetolerance[4–6,20,21],increasedtotal occurred.Oncethoughttobeaninertstoragedepotforexcess cholesterol[8,16,22],anddecreasedstrengthandmobilityin calories,importantonlytoenergyhomeostasis,wenowknow olderadults[23–31].Advancingageresultsinaredistribution that adipose tissue expresses and secretes a multitude of of fat depots, despite stable or decreasing overall fat, with hormonesandproinflammatorycytokinestherebyactingin adiposestoragesiteschangingfromsubcutaneouslocations an autocrine, paracrine, and endocrine manner signaling tothemoreharmfulectopiclocations[3,32,33].Inparticular, the heart, musculoskeletal, central nervous, and metabolic intermuscular adipose tissue (IMAT), an ectopic fat depot systems[1–3].Notalladiposedepotsarealike.Recentstudies foundbeneaththefasciaandwithinthemuscles,maybeof havesuggestedthatthelocation[4–8]andtype[9]ofexcess specificinteresttorehabilitationprofessionals. adiposetissue,ratherthansimplytotalbodyadiposity,may IMAT has been studied in a variety of individuals with beimportantinthesystemicincreaseofcirculatingcytokines metabolic [5, 6, 8, 14, 28, 34–36], orthopedic [37, 38], and andtheriseinmetabolicdiseasessuchasdiabetes[9–14](for neurologic[39,40]conditionscommonlyseeninrehabilita- a more complete review of the types and roles of adipose tivesettings.HighlevelsofIMATareassociatedwithinsulin tissue, see Wronska 2012 and Stehno-Bittel 2008) [1, 9]. resistance [5, 6, 8, 14, 28, 34–36], a loss of strength [23–31], 2 InternationalJournalofEndocrinology and mobility dysfunction [23, 41–43]. High levels of IMAT CT is a fast imaging method that utilizes X-rays for an can be found in many patient populations, including, but indirect measurement of IMAT based on the tissue density notrestrictedto,theparaspinalmusclesofindividualswith of an area. On a continuum of density where bone is the chronic back pain [37, 38] and the locomotor muscles of mostdenseandfatistheleastdense,leanmusclemassfalls individualsdiagnosedwithHIV[44],spinalcordinjury[39], betweenthesetwoextremes.LeantissueseenonaCTscan CVA[40],diabetes[6],andCOPD[45].Furthermore,older canbefurtherdividedintoareasofhigh-densityleantissue adultswithincreasedIMATlevelsinthelocomotormuscles andareasoflow-densityleantissue.High-densityleanisan areknowntoexperienceincreasedlevelsofmuscleweakness, areawherelittlefattyinfiltrationoccurs,andlow-densitylean decreasedmobilityfunction[23,41–43],andanincreasedrisk tissueisanareawhereincreasedlevelsofadipocytesarefound of future mobility limitation [42, 43]. IMAT has potential between and within muscle fibers and result in decreased clinicalimplicationsthatrehabilitationprofessionalsshould densityonCTscan.Anindividualwithahigherproportion recognize and attempt to manage in rehabilitation settings oflow-densityleanisassumedtohaveincreasedlevelsofboth whenworkingwitholderadultsandthosewithdiseasesand IMCLandIMAT.Ifthedensityofamuscleincreases,orthe disabilitiesassociatedwithIMAT. areaoflow-densityleandecreasesafteranexerciseprogram, The purpose of this narrative review is to inform reha- itispresumedthattheexerciseprogramhasresultedinaloss bilitation professionals about the potential metabolic, mus- ofbothIMCLandIMAT. cle, and mobility associations of increased IMAT in the WithMRI,directmeasurementsofIMAT[46]canoccur locomotor muscles of adults. This review will focus on without the use of harmful radiation; therefore, MRI is threeareas.First,thedefinitionandmeasurementofIMAT increasingly used to quantify IMAT [25–27, 29–31, 35, 36, will be presented; second, the implications of increased 39, 46, 54–65]. MRIs utilize the chemical properties of fat locomotor muscle IMAT in metabolism, muscle strength, andmuscletodirectlymeasuretheamountofIMATwithin andmobilitywillbereviewed;andthird,recommendations a region of interest [46]. However, while MRI studies of for future research and treatment for adults with increased IMAT avoid the use of harmful radiation, they do typically levels of IMAT will be made. Literature targeted for this require time-consuming manual segmentation for a region reviewincludedpeerreviewedcross-sectional,longitudinal, of interest. This process can be difficult and less reliable epidemiologic,andclinicalstudiesinadulthumans. for small, irregularly shaped areas. Comparative studies of MRI and CT have demonstrated that MRI has a higher sensitivity than CT for identifying early fatty replacement 2.DefinitionsandMeasurementsofIMAT in muscle and that MRI, because it is not density based, provides better anatomical details of soft tissue than CT IMAT has been referred to in the literature by a variety of [46,66,67].StudiescomparingCTandMRImeasurements namesanddefinitionsincludingmyostasis,intermuscularfat, have generally shown good agreement and both methods intramuscularfat,andlowdensityleantissue.Intermuscular areacceptableprecisemeasuresofIMAT[68,69].Thesame fat is typically the broadest definition of fatty infiltration definitionandmethodformeasuringIMATshouldbeused in the muscle referring to storage of lipids in adipocytes in pre- and poststudies. Both CT and MRI appear to be underneaththedeepfasciaofmuscle.Thisincludesthevisible appropriate and advanced techniques for measuring IMAT; storage of lipids in adipocytes located between the muscle however,drawingconclusionsconcerningabsoluteamounts fibers (also termed intramuscular fat) and also between ofIMATacrossstudiesmaybedifficultifdifferentmethodsof muscle groups (literally intermuscular) [46] (See Figure1). measurementareemployed.Manystudieshaveusedslightly Whilenotfrequentlyisolatedasaseparatefatdepotbyitself, differentdefinitionsofIMAT(i.e.,adiposetissueinamuscle, there also exists a smaller group of lipids stored within the adiposetissuebetweenmuscles,oradiposetissueunderthe musclecellsthemselvesknownasintramyocellularlipidsor fascia of the thigh), and conclusions drawn across studies IMCL;IMCLhasbeenreviewedextensivelyelsewhere[47]. shouldbeinterpretedwithinthiscontext. Increased levels of IMCL are found both in obese insulin resistantindividualsandinhighlytrainedenduranceathletes; these paradoxical findings have led to the conclusion that 3.IMATandMetabolism lipids stored within muscle cells are not always harmful to the cell [47]. For the remainder of this review, the term IMAT is positively associated with insulin resistance and IMATwillrefertoanymeasureoffatbeneaththedeepfascia an increased risk of developing type 2 diabetes [5, 6, 8, 14, of the thigh, not including studies that have used methods 28, 34–36] (Figure2). The link between IMAT and insulin that independently quantify IMCLs (i.e., histochemical or resistancecouldbetheoreticallyattributedtotherelationship spectroscopicmethods). of IMAT and BMI. Generally, as BMI increases so does IMATismostcommonlymeasuredviacomputedtomog- IMAT [7, 21, 23]. However, even when BMI is statistically raphy (CT) or magnetic resonance imaging (MRI). While accounted for, IMAT remains a strong predictor of fasting IMAThasbeenquantifiedinnumerousstudies,itisnotyet glucoseandinsulinlevelsinbothyounger[5]andolderadults routinelymeasuredorquantifiedinclinicalimagingstudies. [6,22,54],suggestingthatthesemetabolicimpairmentsare CT scans have been extensively used to quantify IMAT in notsimplyduetoobesityalone.Comparedtosubcutaneous numerous studies [5, 6, 10, 14, 20, 23, 28, 40, 42, 43, 48– fat,IMATisamuchsmallerfatdepot,accountingforaslittle 52] and were first described by Kelley et al. in 1991 [53]. as8%oftheadiposetissueinthethigh[5].Despiteitssmall InternationalJournalofEndocrinology 3 VAT Subcutaneous fat Subcutaneous fat Fascia Intramuscular fat Intermuscular fat Figure1:Intermuscularfatisgenerallyconsideredtobeanyfat(includingthefatbetweenmusclegroupsandwithinamuscle)foundbeneath thefasciaofamuscleandisthewidestdefinitionforfatbeneaththefasciaofamuscle.Intramuscularfatisthevisiblefatfoundwithinamuscle. Intermuscularisconsideredtobeanectopicfatdepotsimilartovisceraladiposetissue(VAT)foundintheabdomen. Metabolic dysfunction Disease Obesity - Insulin resistance - Inflammation Muscle dysfunction Injury ↑IMAT - Decreased muscle strength - Decreased muscle quality - Decreased muscle activation Age Inactivity Mobility dysfunction - Decreased gait speed - Decreased physical performance - Increased future mobility risk - Increased risk hip fracture Figure2:Muscleinjury,obesity,age,diseasestatus,andinactivityareallfactorsthatareassociatedwithincreasedlevelsofIMAT.Increased levelsofIMATmayalsoleadtoamyriadofmetabolic,muscle,andmobilitydysfunctions. size, IMAT is strongly associated with insulin sensitivity in 4%comparedtothenonpareticlimbinolderstrokesurvivors obeseindividuals[5].ItiscurrentlyunknownifIMATacts [28]. Similar to the findings in older adults with type 2 merely as a marker of metabolic dysfunction or if it may diabetes, a positive relationship also exists between IMAT haveanintermediaryormodifyingroleininsulinresistance. and fasting insulin levels in those post-CVA [28]. In this SinceIMATsitsincloseproximitytothemusclefibers,itis study of 70 adult stroke survivors, we found that decreased possiblethatIMATmayinteractwithmusclefibersthrough muscle attenuation (indicating increased IMAT levels) was a yet unknown pathway leading to muscle dysfunction and associatedwithincreasedfastinginsulinlevels[28].Similar insulin resistance [10, 26]. Muscle dysfunction may lead to results are found in those who have suffered a spinal cord furtherinactivityandincreasedlevelsofIMATprecipitating injury. One study found that thigh IMAT increased on a cycle of increased IMAT, insulin resistance, and muscle average 26% in just three months after a complete spinal dysfunction.Thiscloserelationshipbetweenthemusclefibers cord injury [39]. This large increase in IMAT accounted and IMAT becomes particularly important in populations for a 70% reduction in glucose tolerance in these same thatareknowntohaveincreasedIMAT,muscledysfunction, individuals [39]. The strong relationship observed between and insulin resistance including individuals with diabetes decreasedglucosetoleranceandincreasedIMATpostspinal [70] and survivors of stroke [28, 40] and spinalcord injury cord injury suggests that accumulation of IMAT may have [39,57,58]. a deleterious effect on glucose homeostasis particularly in Afterastroke(CVA),musclevolumedecreasesandboth thosewhoaremobilitylimited.Furtherstudiesarenecessary subcutaneousadiposetissueandIMATincreaseintheparetic to determine if IMAT plays a direct role in decreased limb[28,40].Wenotedthat,inthepareticlimb,thesubcuta- glucose tolerance or if it is only a marker of metabolic neousadiposedepotwas6%higherandIMATwasincreased dysfunction. 4 InternationalJournalofEndocrinology Despite not knowing the specific mechanism behind aging [23–31] (Figure2). Older adults with higher levels of IMAT’spotentiallyharmfulinfluenceonmusclemetabolism, IMATinthelegshavelowermusclestrength[23,30]aswell thereareseverallinesofevidencethatsupportthisrelation- asmusclequality[23]ortheforceproducedperunitofcross- ship.MultipleauthorshavesuggestedthatIMAT,anectopic sectionalareaofmuscle,asdemonstratedbythetwowomen fatdepotsimilartovisceraladiposetissue,mayreleaseahost whose thigh images are presented in Figure3. Decreases in ofproinflammatorycytokinesresultinginlocalinflammation musclequalitymayleadtodifficultiesinfunctionalactivities withinthemuscle[10,26,48,65,71].Otherectopicfatdepots, [75] and several studies have also demonstrated that adults suchasthosefoundintheliverortheabdomen,areknownto with comorbid conditions such as COPD [45], stroke [28], haveincreasedsystemiclevelsofproinflammatorycytokines osteoarthritis[76],kidneydisease[77],andcognitivedecline [72]. Beasley et al. also reported a relationship between the [78] demonstrate decreases in muscle quality. The relation- amount of IMAT within the thigh and systemic measures shipofincreasedlevelsofIMATanddecreasedstrengthand of proinflammatory cytokines, as measured in the serum musclequalityisreportedinmultiplestudiesinthethigh[23] suggesting that IMAT may in fact be related to increased and calf muscles [30], in healthy elders [23], and in adults wholebodyinflammation[10].Wereportedforthe1sttime withcomorbidconditionsincludingdiabetesandperipheral increased IMAT in the paretic leg of stroke survivors [40], neuropathy[30].Itisintriguingthatthisrelationshipdoesnot whichwefollowedwithourexaminationofskeletalmuscle appear to be confined to older adults [26]. After 30 days of TNF-a[73].WefoundthatbothIMAT[40]andinflammation singlelimbsuspension,Maninietal.foundthatyoung(∼20 [73] are increased in the paretic leg of stroke survivors [28, years)healthyindividualsexperiencedanincreaseof15–20% 73].However,todate,weareunawareofanypublishedexam- in IMAT of both the calf and thigh muscles. This increase inations of the direct relationship between IMAT and the inIMATalsoexceededthelossofleantissuesuggestingthat localinflammatoryenvironmentwithinthemuscle.Skeletal IMATwasnotjustmerely“filling”thespaceleftbyleantissue muscleistheprimarysiteforglucosemetabolisminthebody. atrophy[26].TheincreaseinIMATalsoaccountedfora4–6% While it is currently unknown by which mechanism IMAT oflossofstrength,againemphasizingthatIMATismorethan may act on metabolism, it does appear that a relationship aninertstoragedepot,butmayalsoplayaroleininactivity exists between increased levels of IMAT and decreased relatedstrengthloss. whole body glucose metabolism particularly in those who High levels of IMAT are also associated with decreased have suffered an injury that reduces muscle function. It is activationofthequadricepsmusclesinolderadults[31].We theorized that the close proximity of IMAT to the muscle found a moderate significant negative relationship between fiber may impair the local muscle environment through IMATandquadricepsmuscleactivationinasmallsampleof aforementionedincreaseinlocalproinflammatorycytokines olderadults.Muscleactivation,inthisstudy,wasquantified [10, 59], impaired blood flow [5, 8], or increasing the rate bythecentralactivationratio,ameasureofamuscle’sability of lipolysis within skeletal muscle resulting in an increased tofullyactivateduringamaximaleffortvoluntaryisometric concentration of glucose within the skeletal muscle itself, contraction. It appears that not only may IMAT impair a leadingtoinsulinresistance[5,8]. muscle’s ability to produce force but also it may actually hindertheimprovementinmusclequalitytypicallyseenwith resistance training [59]. We examined changes in muscle 4.IMATandMuscleFunction quality after 12 weeks (3x/week) of resistance training in 70 older adults with a history of falls and found that only Thestructuralcompositionofmuscleisanimportantfactor individuals with low amounts of IMAT in the thigh at the initsfunction[23].Itisnowwellestablishedthatalossoflean start of training were able to significantly improve muscle musclemassinolderadultsdoesnotdirectlytranslateintoa quality.Similartothelossofmusclequalitywithhighlevels lossofstrength[41,74].TheBaltimoreLongitudinalStudyof of IMAT, a decrease in muscle activation in the presence Agingfoundthatwhilegripstrengthandmusclemassboth of high amounts of IMAT suggests that IMAT may be declinedwithage,olderadultswereweakerthanthelossof partially responsible for inhibiting muscle force production muscle mass alone would predict [74]. Similar results were andimprovementswithstrengthtraining. found in a 3-year longitudinal study of 1800 healthy older adults. In this finding from the Health ABC Study, muscle strengthdeclinedeveninthoseindividualswhogainedlean 5.IMATandMobilityFunction muscle mass. While lean mass decreased by approximately 1%ayear,strengthdecreasedupto4%duringthesametime Perhapsevenmoreimportantthantheassociationbetween period [41]. This clear dissociation between lean mass and IMATandmusclefunctionistherelationshipbetweenIMAT strength advocates for factors other than lean muscle mass andmobility.Thereisanincreasingamountofevidencelink- being responsible for the declines in muscle function seen ingIMATwithmobilityimpairmentinolderadults[25,27, with aging. IMAT is one such factor that may impact the 29,30,42,43].IncreasedlevelsofIMATareassociatedwith musclefunctionlossesthatareassociatedwithaging. decreased six-minute walk distance [27, 30, 79], decreased An emerging body of literature supports IMAT as a gait speed [43], decreased physical performance [25, 30], significant predictor of both muscle and mobility function difficulty with repeated chair stands [43], and slower stair inolderadultssuggestingthatincreasedIMATmayatleast descentandtimedupandgotests[27].Thisrelationshiphas partially explain a loss of strength and mobility seen with consistentlybeenreportedinavarietyofpopulationsofolder InternationalJournalofEndocrinology 5 Timed up and Stair up Stair down Lower extremity Knee extension go (s) (s) (s) power (W) strength (N) Subject 07 8.4 6.6 7.0 88.2 194.8 Subject 44 6.5 4.9 4.4 139.5 248.3 Difference 25% 29% 45% 45% 24% Subject 07 Subject 44 Lean:99.5cm2 Lean:100.7cm2 IMAT:18.8cm2 IMAT:9.8cm2 Figure3:Twowomenwithsimilarage,BMI,andlevelsofleanmusclemassbutwithdifferinglevelsofIMATinacross-sectionalMRIimage ofthethigh.Subject7hasdoublethelevelofIMAT(blackwithinthemuscle)inherthighassubject44.Whilebothwomenhavesimilarlevels ofleantissue(seeningrey),theyhavedifferentlevelsofmobilityandmusclefunction.TheincreasedlevelsofIMATanddecreasedmuscleand mobilityfunctionofsubject7areconsistentwithliteraturethatreportsthatincreasedlevelsofIMATareassociatedwithdecreasedmuscle andmobilityfunction. adults including healthy elders [43], those with a history of It is clear that increased levels of IMAT are associated diabetes[25,30],COPD[45],falls[27],andcancer[27]. withdecreasedmuscleandmobilityfunctioninolderadults IMAT is frequently associated with mobility function but whether IMAT is a marker of muscle dysfunction or evenwhenleantissueisnotsuggestingthatIMATmayinfact whether it has a direct effect on muscle dysfunction is not beanimportantvariablewhenreferringtomobilityfunction currently known. IMAT may act as an intermediary mod- inolderadults[80].IMATisalsopredictiveoffuturemobility ifying preexisting pathological process as IMAT’s harmful limitations[42].Alargestudyofover3000olderadultsaged relationship with muscle and mobility function has been 70–79 followed up for two and one half years revealed that theoretically attributed to an increase in proinflammatory individualswiththegreatestamountsofbaselineIMATwere cytokines[10,26,48,65,71]similartotheattributedeffects 50to80%morelikelytodevelopmobilitylimitationsoverthe ofproinflammatorycytokinesonmetabolicfunction.Inter- followingtwoandonehalfyearswhencomparedwiththose estingly,severalauthorshavereportedrelationshipsbetween withthelowestlevelsofbaselineIMAT[42].Thisfindingwas increasedproinflammatorycytokinesanddecreasedmuscle consistentevenafteradjustingforbaselinetotalbodyfatand [83, 84] and mobility function [85–87] that are strikingly musclestrength. similar to those reported between IMAT and muscle and High levels of IMAT may not only impair mobility but mobilityfunction[19]. also increase the risk for developing disability. Increased IMAT may also be harmful to muscle and mobility levelsofIMATcorrelatewithlowbonemineraldensityand functionduetomechanicalchangesinmusclethatoccurin an increased risk of hip fracture [81, 82]. IMAT levels of the presence of IMAT that can lead to changes in muscle the mid-thigh are noted to be a strong and independent fiberorientation[56].Studiesofrotatorcuffinjuriessuggest determinantofbonemineraldensity[82].Additionally,the thatthelossofforceinamusclemayberelatedtoincreased HealthABCStudy,alargelongitudinalinvestigationofover levelsofIMAT[56].Afterasupraspinatustear,elasticityofthe 2500individualsbetweentheagesof70and79years,reported muscledecreasesandpassivetensionofthesupraspinatusis a large increase in the risk for hip fracture with increased increased.Thisdecreasedelasticityleadstoapoorerabilityto IMAT [81]. A decrease ofonestandard deviationof muscle activelygenerateforce,resultinginalossofmaximaltension density of the thigh as measured with CT conferred a 50% of the muscle [88]. In addition to the loss of elasticity in increaseinhipfracturerisk[81].Evenafteradjustingforbone rotator cuff muscles, it has been hypothesized that excess mineraldensity,anincreaseinIMATraisedtheriskofahip IMAT leads to an alteration in contractile fiber pennation fractureby40%[81]. angle, hence resulting in an unfavorable mechanical angle 6 InternationalJournalofEndocrinology andaconcomitantreductioninforceproduction[56,89].We youngertoolderathletes[14,64]andwhencomparingobese areunawareofstudiesthathaveexaminedtheeffectofIMAT active to inactive individuals [29]. After 30 days of single on elasticity or of pennation angle in locomotor muscles. limbsuspension,amethodofimmobilizingoneleg,young, WhiletheimpactofIMATrelativetoelasticityorpennation healthyadultsdemonstrateanincreaseof15%IMATinthe angle might be expected to be similar in other muscles, immobilized thigh and 20% in the calf [26]. In a cross- the results from rotator cuff studies should be interpreted sectional study examining master athletes from age 40 to cautiouslyduetodifferencesinthemuscle’sarchitectureand 81 who consistently participated in high levels of physical function.Additionally,fattyinfiltrateinrotatorcuffmuscles activity it was found that younger and older adults did not followsa known musculotendinousinjury,that is,a rotator differ in IMAT levels [26]. Even in a population of obese cufftear.Thecauseoftheincreasedfattyinfiltrationassoci- adults with diabetes and peripheral neuropathy, conditions atedwithmanymetabolicorsystemicdiseasesisnotaseasyto knowntobeassociatedwithincreasedIMAT,therestillexists pinpointasthereisnodirectmuscularinjury.Futureresearch asignificantrelationshipbetweenthenumberofstepstaken should elucidate the mechanisms behind increased IMAT inadayandthevolumeofIMATinthecalf[29].Tuttleetal. anddecreasedmuscleandmobilityfunctioninolderadults reportedthattheaveragedailystepcountwasabletoexplain and importantly should determine if minimizing IMAT is upto19%ofthevarianceinIMATinthecalfofolderadults accompaniedbyimprovedmuscleandmobilityfunction. withdiabetesandperipheralneuropathy[29].Basedonthese studies,itappearsthatIMATmaybeamenabletochangevia increasingphysicalactivitylevels.However,themagnitudeof 6.Aging,WeightLoss,Activity,andIMAT changesreportedquestionstheclinicalsignificanceofthese changes. It may be that significant weight loss, via physical SeveralauthorshaveimpliedthatIMATisanunwantedbut activity or diet, may be necessary to achieve meaningful inevitableconsequenceofagingasepidemiological,longitu- changesinIMAT. dinal, and cross-sectional studies have reported significant Multiplestudieshaveexaminedtheeffectsofdiet,exer- positiverelationshipsbetweenagingandIMAT[7,48,63,90]. cise,oracombinationofdietandexerciseonIMAT[20,22, Some have theorized that whole body IMAT increases as 24,51,52,55,59,61,62,91–100].Mosthavereporteddecreased little as 9grams/year [7] to as much as 70 grams/year [63]. IMAT following intervention [20, 22, 51, 52, 55, 61, 62, 91– The majority of studies examining the effects of aging on 94,96,97,99].Thecurrentgeneralconsensusamongstudies increasesinIMAThavebeensmallandcross-sectionaland examiningchangesinIMATwithweightlossaloneorwith have failed to account for activity levels and disease status exercise is that weight loss is necessary to see significant orhaveinvestigatedonlyanarrowagerange.Thesecaveats changesinIMAT[20,51,52,55,62,91–93,97].However,itis call into question the definitive assertion that IMAT is an possiblethatexercise,whenperformedatasufficientintensity inevitable consequence of aging [7, 63, 90]. In the largest and duration to induce weight loss, is actually superior at longitudinalstudytodate,Delmonicoetal.followedupover decreasingIMATlevelscomparedtoweightlossinducedby 1600olderadultsbetween theagesof70and79for5-years reducedcalorieintake[55,62,97].Murphyetal.compared [48].Afteraccountingforrace,weightchanges,healthstatus, the effects of exercise induced weight loss to weight loss andactivitylevels,theyfounddecreasedthighmuscledensity induced by calorie restriction alone in overweight adults even in those who lost weight or were weight stable over a aged50–60[62].Theyfoundthatwhenexerciseresultedin 5-yearperiod.However,itshouldbenotedthatincreasesin weight loss, the loss of IMAT was two times greater than IMATwereclearlyinfluencedbyincreasesinbodyweightas calorie restriction alone. This finding is in agreement with thosewhogainedthemostbodyweightoverfiveyearsalso Christiansenetal.whofoundthatthecombinationofcalorie gainedthemostIMAT.Furthermore,thestudydidnotreport restrictionandexerciseresultedinan11%decreaseinIMAT thereasonsforlossofbodyweight(i.e.,illness).Weightloss while calorie restriction alone resulted in a 7% decrease in due to intentionalcaloric restrictionand exercise may have IMAT[55].Whileweightlossmaybenecessarytodecrease adifferentinfluenceonIMATthanweightlossduetoillness IMAT, this may not be a desirable option for some older asnumerousinterventionstudieshavefoundthatintentional adults.Weightlossinfrail,olderadultswithalreadylowbody weightlossleadstodecreasesinIMAT[52,62,91,92]. massindexesmaybeaccompaniedbylossofmusclemassand More recent work suggests that increases in IMAT may functionandthereforemaynotresultinapositiveoutcome. bemoreaproductofillness,disuse,orinactivitythanaging There is currently a paucity of literature that examines the perse[24,29,64].Thisisaclinicallyimportantfindingasit effects of any intervention on IMAT in frail, older adults. suggeststhatIMATmaybeamenabletochangeviaaphysical MoststudiesofIMATtodatehaveexaminedyounger[22,55, activity intervention (Figure4). Longitudinal twin studies 92,95,96],obese,[22,52,55,91–93],oroverweight[20,22, havedemonstratedthatafter32yearsofdifferenceinactivity 51,52,62,91,94–96,101]populations,makinggeneralization habits, inactive twins had 54% higher IMAT in their mid- tofrail,olderadultsdifficult.Goodpasteretal.reportedthat thigh compared to their more active twin [35]. High levels physicalactivitynearlyamelioratedtheincreaseinIMATthat of spasticity after spinal cord injury have also been shown occurswithsedentarybehaviorinolderadultswithamean to protect against the accumulation of IMAT [57]. Further ageof76years[24].Amodestwalkingprogramof1-2times support for the assertion that physical activity has a strong per week for as little as 30 minutes per session stabilized influence on IMAT is found in studies of young, healthy IMATaccumulationintheseindividuals.Incontrast,inthis adultsfollowingperiodsofinactivity[26],whencomparing samestudy,thecontrolgroupthatdidnotparticipateinany InternationalJournalofEndocrinology 7 Metabolic - Increased insulin sensitivity Disease Obesity - Decreased inflammation Exercise and Muscle Injury ↑IMAT weight loss - Increased muscle strength - Increased muscle quality Age Inactivity Mobility - Increased gait speed - Improved physical performance Figure4:ExerciseandweightlossmayacttodirectlydecreaseIMAT,improvefactorsassociatedwithincreasedIMATsuchasobesityand inactivity,andimprovemetabolic,muscle,andmobilitydysfunction. formal exercise program experienced an 18% gain in thigh IMATwithinthemuscle.Thishasyettobeexploredandis IMATover12months[24].Thissuggeststhatphysicalactivity currentlyonlyspeculative. might mitigate the accumulation of IMAT in older adults. Another promising direction that may yield new thera- However,onlytwosmallstudieshavefoundthatincreasing peutic targets is research into the origins of IMAT. Studies physicalactivity,onethroughwalkingandtheotherthrough investigating the cellular origins of IMAT [102, 103] are resistance training, decreased IMAT in this population [93, attemptingtodeterminethecellularprocessesthatprecipitate 94].WealsofoundthatresistancetrainingdecreasedIMAT increasedIMAT.Whiletheseoriginsarecurrentlyunknown, in the thigh muscles of older adults (∼65 years) who had iffoundtobesimilartootherectopicfatdepotssuchasthose a CVA [101]. This is a promising finding as it suggests that found in the liver, pharmacological interventions used in IMATmayrespondtophysicalactivityinterventions,evenin combinationwithexercisemaybeatreatmentoptionworth olderadultswithcomorbidhealthconditions.However,more future exploration [72]. Current recommendations for the researchisneededto(1)verifythesefindings,(2)determine treatment of nonalcoholic fatty liver disease that results in themosteffectivemethodofreducingIMAT,and(3)assess the accumulation of fat within the liver, similar to IMAT theclinicalimpactofdoingsoinolderadults. accumulationinthemuscle,includethecombinationofdiet, exercise, and in some cases medication [72]. While we are unawareofanytrialsexaminingtheeffectsofmedicationon 7.FutureDirectionsand IMAT,theuseofanti-inflammatoryorothermedicationsthat RehabilitationConsiderations havebeeneffectiveattreatingotherectopicfatdepotssuchas thiazolidinedionesmaybeusefulinthetreatmentofIMAT, More work is necessary to determine the role of increased particularlyinolderfrailadults[72]. IMAT on metabolic, mobility, and muscle dysfunction. It Large randomized control trials examining the effect of has not yet been determined if IMAT is merely a marker exercise on decreasing IMAT are limited, though it does of dysfunction or if it has some direct or indirect role appear that physical activity, at a minimum, may serve as in modifying metabolic, muscle, and mobility function. If a preventive strategy to halt the infiltration of IMAT into IMATdoesimpairmuscleactivation,thenusingexerciseasa muscle [24] and may even decrease IMAT in muscles that methodtoreduceIMATmayhavealimitedeffectparticularly havealreadyundergonethisabnormaladaptation[20,22,51, in frail, older adults. Impaired muscle contraction may 52,55,61,62,91–94,96,97,99].Themajorityofstudiesthat minimize the muscles ability to mobilize and utilize IMAT havedemonstratedadecreaseinIMAThavebeenstudiesthat as a fuel source, and it is possible that a combination of employed a combination of calorie restriction and aerobic therapies will be necessary to reduce IMAT. This may be exercise for at least 6 months [20, 51, 52, 62, 91, 93, 96]. particularlytrueinfrail,olderadultswithlimitedabilityor It also appears that resistive exercise alone [94, 101] or in need to change their body mass. The addition of electrical combinationwithweightloss[97]oraerobicexercise[55,61] stimulationtoexercisemaybeonemethodtoreduceIMAT maydecreaseIMAT. and improve muscle function. In a small study of nine It is theorized that exercise training may access IMAT individualswithcompletespinalcordinjurywhichcompared as a fuel source during times of increased activity of the the use of electrical stimulation on the quadriceps muscles muscle[20,30].Whilespeculative,IMATmaybepreferen- twiceaweekfor12weekscombinedwithcalorierestrictionto tially metabolized as a fuel source to support the increased calorierestrictionalone,theadditionofelectricalstimulation demandsofthemusclethusresultinginadecreaseofIMAT was shown to significantly decrease IMAT [58]. While the with long-term activity [20, 30]. While exercise should be decrease in IMAT was still relatively small (approximately a lifelong activity, to decrease IMAT levels a minimum of 3%); particularly noteworthy is the observation that the 12 weeks of interventionappears to be required to decrease calorierestrictiongroupincreasedIMATby3%duringthis IMAT, though 6 months may be superior. It is important same period of time [58]. 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