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-Hydroxy--Methylbutyrate(HMB)

1

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Educa7onalObjec7vesforthe

-Hydroxy--Methylbutyrate(HMB)Presenta7on

ProvideageneraloverviewofHMBintakeandmetabolism Describemechanis;cstudiesoftherolesofHMBincellsignalingpathwaysgoverningbothmuscleproteinsynthesisanddegrada;on DiscussroleofHMBinreducingmuscledamageduringexercise

Reviewclinicaldataevalua;ngchangesinbodycomposi;onandperformanceinathletesreceivingHMBsupplementa;on

Usedaloneandincombina;onwithcrea;neorotheraminoacids Includingeffectsinhealthy,olderadults

Presentothertherapeu;candmedicalapplica;onsAddressthesafetyofHMBsupplementa;on

2

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3

Generaloverviewofintakeandmetabolism

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WhatIsHMB?

HMBisaleucinemetabolite Leucineisanessen;albranched-chainaminoacidthatcantriggermuscle

proteinsynthesisandmayinhibitproteindegrada;on1

Isitunknownwhetherleucineoritsmetabolitesac;velypar;cipateinproteinsynthesis/degrada;on

Leucineistransaminatedto-ketoisocaproate(KIC)bybranched-chainaminoacidtransferase,mainlyinmuscle;ssues

Approximately5%to10%of-ketoisocaproate(KIC)isconvertedtoHMB(byKIC-dioxygenase)inthecellcytosol

CalciumHMBhasthefollowingmolecularstructuralformula2

1. NemetD,etal.IMAJ.20057:328-332.2. Availableat:www.chemblink.com/products/135236-72-5.htm.AccessedMay10,2011.

Ca++HO O

O

O

O OH

4

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Forma7onofHMBDuringLeucineMetabolism

AdaptedwithpermissionfromNissenSLandAbumradNN.JNutrBiochem.19978(6):300-311.

Leucine

KIC Isovaleryl-CoA

-methyl-crotonyl-CoA(MC-CoA)

-hydroxy--methylbutyrate

(HMB)

HMB-CoA

HMG-CoA

Mevalonate

Acetyl-CoACholesterol

(5-10% of

Leu metabolism)

Acetoacetyl-CoA

(only when

biotin is deficient)

5

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SourcesofHMBintheDiet

Catabolismofleucine Meanintakeofleucinefromfoodandsupplements(1988-1994NHANESIII)was6.1g/day1

Assuming5%to10%conversioninthebody,thisrepresents0.3to0.6gHMBperday

Togetthe3-gHMBdosetypicallyusedinresearch,30-60gleucine/daywouldhavetobeconsumed

HMBinfoods TherearetracesofHMBinmanyanimal-andplant-basedfoods,especially

ca_ishandalfalfa2

1. Ins;tuteofMedicineoftheNa;onalAcademies.DietaryReferenceIntakesforEnergy,Carbohydrate,Fiber,Fat,FayAcids,Cholesterol,Protein,andAminoAcids.Washington,DC:TheNa;onalAcademiesPress2005:1008.

2. Availableat:hp://www.webmd.com/heart-disease/news/20000818/researchers-take-closer-look-at-supplement-sensa;on.AccessedMay10,2011. 6

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HMBAbsorp7onandKine7cs

ThemechanismofHMBabsorp;onfromtheintes;nehasnotbeenreported

In2kine;ctrials,plasmahalf-lifewas2.5hours HMBlevelsreturntobaselineat~9hoursaeringes;on Upto30%ofanoralHMBdoseisexcretedunchangedintheurine

Theaddi;onofglucosetoacalciumHMBsupplementdoesnotincreasebioavailabilityorcellularuptakeofHMB AddedglucosedoesslowHMBabsorp;onthroughdelayedgastric

emptying

VukovichMD,etal.JNutrBiochem.200112(11):631-639.7

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HMBBioavailability

ReprintedfromFullerJCJr,etal.BrJNutr.2011105:367-372.

BioavailabilityofafreeacidgelformwasgreatervscalciumHMBcapsules 2studies,eachwith8healthyadults(4male,4female) 3treatments 1gcalciumHMBincapsuleform

EquivalentamountofHMBinfreeacidforminagel(swallowedimmediately) FreeacidHMBgelheldsublinguallyfor15sec,thenswallowed

BloodandurinaryHMBlevelsweremonitoredfor3to24hoursaeringes;on Onlycommerciallyavailableformiscalciumsalt

aP

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9

Mechanismsofac7on

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PossibleHMBMechanismsofAc7on

HMBmaybeanan;catabolicagent Studieshavedocumentedpoten;allyinhibitedpathwayssuchasthe

ubiqui;n-proteasomepathwayinamurinemodel1,2

HMBmaybeasubstrateforcholesterolsynthesisinmuscle3 Forma;onof3-hydroxy-3-methylglutarylCoenzymeA(HMG-CoA,precursor

forcholesterolsynthesis)

Muscleisdependentoncholesterolsynthesistomeetitsneeds Increasedcellmembraneintegritywithimprovedmusclecholesterol

synthesis

StressedorinjuredmusclecellsmightnotsynthesizeenoughcholesterolHMBalsohelpstos;mulateproteinsynthesisviathemTORpathway4

Maybetherealfactorbywhichleucines;mulatesproteinsynthesisHMBmayhaveothereffects(eg,immunomodulatoryorhormonal)5

1. LeckerSH,etal.JNutr.1999129:227S-237S.2. SmithHJ,etal.CancerRes.200565:277-283.3. NissenSLandAbumradNN.JNutrBiochem.19978:300-311.4. EleyHL,etal.AmJPhysiolEndocrinolMetab.2008295:E1409-E1416.5. ZanchiNE,etal.AminoAcids.201140(4):1015-1025.

10

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TheUbiqui7n-ProteasomePathwayforProtein

Degrada7on

ReprintedfromLeckerSH,etal.JNutr.1999129:227S-237S.11

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EffectsofHMBontheUbiqui7n-ProteasomePathway

ReprintedfromSmithHJ,etal.CancerRes.200565:277-283.

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EffectsofHMBonProteinSynthesisandDegrada7on

Initiator (PIF, LPS, TNF- , angiotensin II, etc.)

Caspase-8

Caspase-3

PKR

p38 MAPKPKR P

eIF2 eIF2 P

Translational efficiency

Protein synthesis

ROSNF- (nuclear accumulation)

Proteasome + E3 mRNA

Protein degradation

HMB blocks pathway

here

X

PIF,proteolysis-inducingfactorLPS,lipopolysaccharideTNF,tumornecrosisfactorPKR,RNA-dependentproteinkinaseMAPK,mitrogen-ac;vatedprotein

kinaseNF,nuclearfactorROS,reac;veoxygenspecieseIF,eukaryo;cini;a;onfactorP,phosphorylated.

BasedonEleyHL,etal.AmJPhysiolEndocrinolMetab.2008295:E1417-E1426.

13

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FurtherEffectsofHMBonCellularProteinSynthesis

HMBincreasesmTORsignalingpathwayac;vity

mTORincreasesprotein

transla;on

Promotesit Keepsitfrombeingturnedoff

EleyHL,etal.AmJPhysiolEndocrinolMetab.2008295:E1409-E1416.

AdaptedfromSABiosciences,aQIAGENcompany.Availableat:hp://www.sabiosciences.com/pathway.php?sn=mTORPathway.AccessedJune27,2011.14

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0.90.80.7

0.60.50.4

0-2D

ensitometryunits,

ph/tot

a

0.30.20.1

-1 0 2Time, h

p mTOR

Total mTOR

1.6

1.41.21.00.8

0-2

Densitometryunits,p

h/tot

b

0.60.40.2

-1 0 2Time, h

p P70S6K

Total P70S6K

EffectsofHMBonPhosphoryla7onStatusofmTOR

PathwaySignalingFactors

ReprintedfromEleyHL,etal.AmJPhysiolEndocrinolMetab.2007293:E923-E931.

HMB (50 M) added here to murine myotubes.

HMBincreasedphosphoryla;onofmTORsignalingfactors,s;mula;ngproteinsynthesis

HMBaenuatesthedepressiveeffectsofproteolysis-inducingfactoronproteinsynthesis

aDifferentfromcontrol,P

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16

HMBandindicatorsofmuscledamage

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EvidenceforaProtec7veEffectofHMBAgainstMuscle

CellMembraneDisrup7on

Exercisecanresultinmusclecellmembranedisrup;on1,2Eleva;onsofcrea;nekinase(CK)andotherenzyme(eg,lactatedehydrogenase[LDH])levelsinthebloodcanbeindicatorsofmusclecellmembranedisrup;on3,4

NotnecessarilymuscleproteinbreakdownAfewexercisestudieshavefoundabluntedCKresponseduringHMBsupplementa;on5,6

1. McBrideJM,etal.MedSciSportsExerc.199830(1):67-72.2. HurleyBF,etal.IntJSportsMed.199516(6):378-384.3. CabanissCD.In:WalkerHK,HallWD,HurstJW,eds.ClinicalMethods:TheHistory,Physical,and

LaboratoryExaminaKons.3rdedi;on.Boston:Buerworths1990:Chapter32.

4. SarriE,etal.BiochemJ.2006394(pt1):325-334.5. KnierAE,etal.JApplPhysiol.200089:1340-1344.6. vanSomerenKA,etal.IntJSportNutrExercMetab.200515(4):413-424.

17

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18/55

EffectofHMBSupplementa7ononCrea7neKinaseLevels

DuringExercise

KnierAE,etal.JApplPhysiol.200089:1340-1344.

Studyinvolving13par;cipants(5male,8female)thathadahistoryofrunningatleast48km/wk

Par;cipantsreceived3gHMBorplacebodailyfor6weeksbeforeaprolongedrun(double-blind)

Pair-matchedbasedonbest2-milerun;me Therunwas20kmonacollegiatecross-countrycourse

CKandLDHweremeasured2weeksbeforetherun(Pre),immediatelyaertherun(Post),andat1,2,3,and4daysaertherun

Results follow on next slide

18

ff f

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EffectofHMBSupplementa7ononCrea7neKinaseLevels

DuringExercise(Contd)

ReprintedfromKnierAE,etal.JApplPhysiol.200089:1340-1344.

MaineffectfortreatmentinCKmeasurement, P=.05,withnosignificantgroup;meinterac;on

AsignificantmaineffectfortreatmentinLDHmeasurement( P=.003),withnosignificantgroup;meinterac;on

450

400

350

300

250

0Pre

CPKactivity,U/L

200

150

100

1dPost

3dPost

Post 2dPost

4dPost

Time relative to the prolonged run

50

Placebo

HMB

19

ff f l 7 l

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EffectsofHMBSupplementa7ononMuscleDamage

DuringExercise

1studyshowedposi;veeffectsof3gHMBand0.3gKIC/dayversusplacebowhenreceivedfor2weekspriortoexercise(bicepscurlwithprolongedeccentricphase) 1

In6nonresistance-trainedmalesubjects Supplementa;onreducedthedelayedonsetofmusclesoreness(DOMS)ra;ngs

(P

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21

EffectsofHMBonbodycomposi7onandstrength

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HistoricalBackgroundonHMBSupplementa7on

NumerousstudiesofHMBsupplementa;oninseveralanimalmodels(steers,lambs,rats,chickens,trout,andhorses)showedposi;veeffects

on

Carcassquality,proteinmetabolism,immuneresponse,muscledamage,an;oxidantstatus,andbloodlipidprofile

Dr.SteveNissen(AnimalScience,IowaStateUniversity)isessen;allythefatheroftheHMBstory

Performedini;alhumanstudiesofHMBsupplementa;oninthe1990s 1 Alsoperformedameta-analysisofsupplementa;onstudiesin2003with

respecttoeffectsonleanbodymassandstrengthgains 2

1. NissenS,etal.JApplPhysiol.199681(5):2095-2104.2. NissenSLandSharpRL.JApplPhysiol.200394:651-659.

22

Ch i O ll M l St th D i HMB

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ChangeinOverallMuscleStrengthDuringHMB

Supplementa7on:Ini7alStudy

ReprintedfromNissenS,etal.JApplPhysiol.199681(5):2095-2104.

aP

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ChangeinUrinary3-Methylhis7dine(3-MH)Excre7on

DuringHMBSupplementa7on:Ini7alStudy

ReprintedfromNissenS,etal.JApplPhysiol.199681(5):2095-2104.EliaM,etal.BrMedJ.1981282:351-354.

3-MHisamuscle-specificaminoacid Formedduringbreakdownofmuscleproteins(ac;nandmyosin) Excretedunchangedinurine

HMBsupplementa;onreducedthephysiologicincreasein3-MHduringexercise

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ChangeinFat-FreeMassDuringHMBSupplementa7on:

Study2

Totalbodyelectricalconduc;vity(TOBEC)wasusedforbody

composi;onanalysis

HMBsupplementa;onincreasedfat-freemassearlyinexercise

regimencomparedwithplacebo

Significantgainscon;nuedthroughday39

ReprintedfromNissenS,etal.JApplPhysiol.199681(5):2095-2104.

32healthyadults(19-22yearsmeanbodyweight,99kg),almostallengagedinanexerciseprogrambeforestudyentryandateatuniversitytrainingtable

Randomizedtoplaceboor3gHMBperdayfor7weeks HMBprovidedinanutrient/proteinpowderplacebowasisocaloricorangejuice

Par;cipantsatenormaldiet(nostrictdietarycontrol) Dailyproteinintakewases;matedat200g(HMB)vs180g(placebo)

Par;cipantsliedweights2to3hours/day,6days/week

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Posi7veEffectsofHMBSupplementa7ononStrength,

Power,and/orBodyComposi7on

26

StudyDesign Treatment Training Results

Double-blindin

untrainedcollege

men,N=371

0,38,or76mg/kg/

dayHMB(equivalent

to0,3,or6g/day)for8wks

Resistance,

3;mes/wk(80%1-

RM)assessedevery2wks

Comparedwithother2groups,Fat-freemassincreasedinthe38mg/kgdosegroup(P

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StudiesShowingNoEffectsofHMBSupplementa7onon

StrengthandBodyComposi7on

27

StudyDesign Treatment Training Results

Randomized,double-

blindinexperienced

(5.5years),

resistance-trained

athletes,N=401

0,3,or6g/dayHMB

for28daysina

carbohydrate/protein

powder

Maintained

individualized

resistancetraining

program(~7hrs/wk)

andkepttraining

logs

NeitherdoseofHMBinfluencedStrength(1-RM)Bodycomposi;on(bydualenergyX-rayabsorp;ometer)Bodyanabolic/catabolicstatusBloodchemistries

Randomized,double-

blindinna;onal-level

athletes(polo,17

rowers,10)with2yearsofresistance

training,N=272

3g/dayHMB(;med-

releaseorstandard

capsule)orplacebo

for6wks

Resistance,

2-3;mes/wk

(Pre-compe;;on

phaseoftraining)

NeitherdoseofHMBinfluencedStrengthBodycomposi;onCrea;nekinaselevels Trendtowardhighercrea;nekinaselevelinplacebogroup(P=.07forgroupx;meinterac;on)

Randomized,

crossoverin

collegiatefootball

players,N=353

3g/dayHMBor

placebofor4wks

(16playersgotHMB

first,19gotplacebo

first)

Intensiveresistance,

20hrs/wkand

variousothertypes

Nochangesinbodycomposi;onorstrengthforeitherplaceboorHMBgroupsLackofchangeinplacebogroupsuggestsovertraining

Randomized,single-

blindincollegiate

footballplayers,

N=264

3g/dayHMBor

placebofor10days

Preseasontraining

campNochangesbetweenbaselineandposttrainingineitherplaceboorHMBgroupsforanaerobicpower

NochangesbetweenplaceboandHMBgroupsforchangesincrea;nekinase,myoglobin,

testosterone,orcor;sollevels

Abbrevia;ons:RM,repe;;onmaximum.1.KreiderRB,etal.IntJSportsMed.199920(8):503-509.2.SlaterG,etal.IntJSportNutrExercMetab.200111(3):384-396.3.RansoneJ,etal.JStrengthCondRes.200317(1):34-39.4.HoffmanJR,etal.JStrengthCondRes.200418(4):747-752.

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WhytheDiscrepancyinHMBStudies?

Therearepoten;aldifferencesinmusclemetabolismbetweenmorehighlytrainedanduntrainedathletes

Morepoten;alforbenefitprobablyinuntrainedathletesLengthofHMBsupplementa;onmayhavebeeninsufficientinnega;vestudies

Morehighlytrainedathletesmightrequirelongersupplementa;on(only1nega;vestudy>4weeksdura;on)

Verylimiteddata(only2studies)onHMBdosesover3g/day Largerbodysizemightrequirealargerdose

TypeoftrainingmaybeimportantDifferencesbetweenlaboratoriesThereareseveralgoodmeta-analysesandreviewsofHMBandathle;cperformance1-6

1. PortalS,etal.JPedEndocrinolMetab.201023(7):641-650.2. ZanchiNE,etal.AminoAcids.201140(4):1015-1025.3. AlonT,etal.ResCommMolPatholPharmacol.2002111(1-4):139-151.4. NissenSLandSharpRL.JApplPhysiol.200394:651-659.5. RowlandsDSandThomsonJS.JStrengthCondRes.200923(3):836-846.6. WilsonGJ,etal.NutrMetab.20085:1DOI:10.1186/1743-7075-5-1.

28

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CounterfeitHMB?

Theini;alhumanresearchonHMBcamefromSteveNissenslaboratoryatIowaState

Thecompoundtheystudiedandtheoneintheirassociatedpatentscalcium-hydroxy--methylbutyrate

AproductmarketedintheUK(HMB-1000,MaximuscleLtd.)hasbeenshowninonestudytobeineffec;veatreducingexercise-

inducedmuscledamage1SubsequentanalysisoftheHMB-1000productrevealedthatitactuallycontainednoHMB2

Itcontainsarelatedleucinemetabolite(calciumhydroxy-methylbutyrate)Thisraisesthepoten;alissuethatsomenoeffectstudieswithHMBcouldbeduetouseofaproductthatdoesnotcontainHMB,butrathersimilarcompoundsthatmightnothavethesamebiologicalac;vity

1Nunan et al. J Strength Cond Res 2010;24:531-537.2Abumrad NN, Rathmacher JA. J Strength Cond Res 2011:25(7):1-2.

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30

HMBandaerobicperformance

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HMBandMeasuresofAerobicCapacity

MostoftheresearchregardingHMBhasfocusedonstrengthandbodycomposi;on

AbilitytotrainharderwithlessmusclebreakdownfromexercisemaybeamechanismthroughwhichHMBcouldfacilitateaerobicperformance

2studieshaveevaluatedaerobiccapacityduringHMBsupplementa;on1,2 Inthesestudies,themechanismofhowHMBmightworkisnotclear

1. VukovichMDandDreifortGD.JStrengthCondRes.200115(4):491-497.2. LamboleyCR,etal.IntJSportNutrExercMetab.200717(1):56-69.

31

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MeasuresofAerobicCapacity:Study1

Randomized,double-blind,crossoverstudyinvolving8endurance-trainedcyclists

Received3g/dayHMB,leucine,orplaceboforthree2-weeksupplementa;onperiods,with2-weekwashoutperiodsinbetween

Par;cipantsperformedgradedcycleergometrytests VO2peak,VO2max,andlactateaccumula;onpeakweresimilarbetweenall

groups

Onsetofbloodlactateaccumula;on(VO2atbloodlactatelevelof2mM)wasincreasedinboththeHMBandleucinegroupscomparedwiththeplacebogroup(9.1%,2.1%,and0.8%,respec;vely)

Leucinehadnoothernotableeffectsonaerobicparameters Lactatethreshold(%VO2max),and;metoreachVO2peakwerealso

increasedintheHMBgroupcomparedwiththeleucineandplacebogroups

BloodHMBlevelsweremuchlower(40-to60-fold)intheleucinegroupversustheHMBgroup

SupportspreviousdataonlowconversionratesofleucinetoHMBVukovichMDandDreifortGD.JStrengthCondRes.200115(4):491-497.

32

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MeasuresofAerobicCapacity:Study2

Randomizedstudyinvolving16collegestudents

Received3g/dayHMBorplacebofor5weeks

Studentsperformedintervaltraining3;mes/weekonatreadmill Comparedwiththeplacebogroupat5weeks,theHMBgrouphad

IncreasedVO2max(13.4%vs8.4%forplaceboP

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34

HMBstudieswithcrea7neorwithaminoacids

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HMBinCombina7onWithCrea7ne

Anaturalques;oniswhethersynergis;coraddi;veeffectswilloccurduringsimultaneoussupplementa;onwithcrea;neandHMB

Clinicaldatahavereportedmixedresults Randomized,double-blindstudyinvolving40volunteers

Received3g/dayHMB,20g/dayfor7daysfollowedby10g/dayfor14dayscrea;ne(Cr),crea;neplusHMB(CrHMB),orplacebofor3weeks

Volunteersperformedprogressiveresistancetraining Leanbodymassgains(assessedviabioelectricimpedance)were0.92kg,0.39kg,and1.54kggreaterforCr,HMB,andCrHMBgroups,respec;velycomparedwithplacebo

SignificantmaineffectforCrgroup(P=.05),andatrendforHMBgroup(P=.08) Datawereaddi;ve,noCrHMBinterac;on(P=.73)

Similarresultswerereportedforstrengthgains,withaddi;veeffectsforCrandHMB Reduc;oninexercise-inducedcrea;nephosphokinaselevelswasgreatestinthe

HMBgroup(maineffect,P=.01) Addi;onofcrea;neantagonizedtheHMBeffect( P=.04forCrHMBinterac;on)

JwkoE,etal.NutriKon.200117(7-8):558-566.35

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HMBinCombina7onWithCrea7ne

Randomizedstudyinbasketballplayers1 Receivedcrea;ne,HMB,crea;neandHMB,orplacebofor30days

Doseswerenotspecified Playersinthecombina;ongrouphadincreasedmaximumpowerandtotal

workoutputcomparedwiththeothergroups

Noaddi;onalincreaseinlactateorfallinmusclepH2studiesdidnotshowbenefitsofthecrea;ne/HMBcombina;on

2,3

Bothstudieswerein57eliterugbyplayers(N=30N=27) Received3g/dayHMB,3g/daycrea;ne,crea;neandHMB,orplacebofor6

weeks

NobenefitswereobservedonMuscularstrengthandendurance

Legpower Anthropometry Aerobicability Anaerobicability

1. ZajacA,etal.JHuminet.200310:95-108.2. OConnorDMandCroweMJ.JStrengthCondRes.200721(2):419-423.3. OConnorDMandCroweMJ.JSportsMedPhysFitness.200343(1):64-68.

36

HMB in Combina7on With the Amino Acids Arginine

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HMBinCombina7onWiththeAminoAcidsArginine,

Glutamine,andTaurine

Randomized,double-blindstudyinvolving17healthymenwhowererecrea;onallyac;ve(noresistancetraininginprevious6months)

ReceivedHMBplusaminoacids(MA)oranisonitrogenouscontroltwicedailyfor12weeks

MAformula=1.5gHMB,7gglutamine,7garginine,3gtaurine,5.8gdextrose Control=10gglycine,11.5galanine,1.5gglutamate,1.5gserine

Volunteersperformedresistancetraining3;mes/week(10exercisesforwholebody) Onelight(12-to14-repe;;onmaximum[RM]),1moderate(8-to10-RM),and

1heavy(3-to5-RM)dayeachweek

Outcomevariables Strength(1-RM) Ver;caljumppower Hormonalandmuscledamageresponsestoanacuteboutofresistance

training

Bodycomposi;onandcircumferences Tendonsize

ResultsfollowonnextslidesKraemerWJ,etal.MedSciSportsExerc.200941(5):1111-1121.

37

Body Composi7on Changes During Supplementa7on

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BodyComposi7onChangesDuringSupplementa7on

WithHMBandAminoAcids

aSignificantdifferencefromV1,P.05bSignificantdifferencefromcontrol,P.05

Abbrevia;ons:V1,beforetrainingV5,aer6wksV8,aer12wks.

KraemerWJ,etal.MedSciSportsExerc.200941(5):1111-1121.

Bodymassandleanbodymasscon;nuouslyincreasedinbothgroups Bodyfatcon;nuouslydecreasedinbothgroups Aer12weeksoftraining,thesupplementa;ongrouphadsignificantlyimprovedbodycomposi;on

a

95

90

85

80

75

70V1 V5 V8

Time point

Bodymass,kg

a,b

CON

MA

A

a

80

75

65

60

55

50V1 V5 V8

Time point

Leanbodymass,kg

a,b

B

a

32

30

26

22

1816

V1 V5 V8Time point

Bodyfat,%

a,b

C

28

24

20

70

CON

MA

CON

MA

38

Strength and Power Changes During Supplementa7on

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StrengthandPowerChangesDuringSupplementa7on

WithHMBandAminoAcids

aSignificantdifferencefromV1,P.05bSignificantdifferencefromcontrol,P.05

Abbrevia;ons:V1,beforetrainingV5,aer6wksV8,aer12wks.

KraemerWJ,etal.MedSciSportsExerc.200941(5):1111-1121.

Bothmusclestrengthandpowercon;nuouslyincreasedinbothgroups Aer6weeksoftraining,thesupplementa;ongrouphadsignificantlyimprovedmusclestrengththatremainedenhancedatthe12-weekassessment

At12weeks,thesupplementa;ongrouphadsignificantlyimprovedmusclepower

140

120

100

80V1 V5 V8

Time point

Squat,kg

A

120

80

60

V1 V5 V8Time point

Bench,kg

B

6000

5000

4500

3500

3000V1 V5 V8

Time point

Verticaljumppower,w

C

5500

4000

100

a

a,b

a,b

a

a,b

a

CON

MAa,b

a

a,b CON

MA

CON

MA

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Changes in Hormone Levels and Indicators of Muscle Damage

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ChangesinHormoneLevelsandIndicatorsofMuscleDamage

DuringSupplementa7onWithHMBandAminoAcids

Comparedwiththeplacebogroup,thesupplementa;ongrouphad Increasedres;ngandexercise-inducedtestosteronelevels Increaseres;nggrowthhormoneconcentra;ons Reducedpre-exercisecor;solconcentra;ons Aenuatedcircula;ngcrea;nekinaseandmalondialdehydeconcentra;ons

Indica;veoflessmuscledamage Ingeneral,theeffectsfromsupplementa;ononcrea;nekinase,malondialdehyde,andcor;solweremorepronouncedatthe12-week

pointinthestudy

Nodietaryintakedatawerereportedforthestudy

KraemerWJ,etal.MedSciSportsExerc.200941(5):1111-1121.40

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41

HMBintheelderly

andtherapeu7c/medicalapplica7ons

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HMBintheElderly

Thereareanumberofnutri;onalproblemsintheelderlypopula;onforwhichtheremaybeapplica;onsforHMB

Sarcopeniaduetoagingandinac;vity1 Bedrest Inabilitytoperformexercisethatcanhelpmaintainmusclemass

Woundhealing(eg,decubi;)2 Presenceofdiseasestates(eg,cancer,conges;veheartfailure)associated

withsignificantcachexia3,4

Generalizedmalnutri;on5HMBhasbeenstudiedinbothhealthyelderlyandthosewithvariouscondi;onsassociatedwithlossofmusclemassandwoundhealingcapacity

1. BaierS,etal.JPENJParenterEnteralNutr200933(1):71-82.2. WilliamsJZ,etal.AnnSurg.2002236(3):369-375.3. HsiehLC,etal.AsiaPacJClinNutr.200615(4):544-550.4. MayPE,etal.AmJSurg.2002183(4):471-479.5. HsiehLC,etal.AsiaPacJClinNutr.201019(2):200-208.

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BodyComposi7onandProteinMetabolisminHealthy

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ody Composi7on and Protein Metabolism in Healthy

OlderAdultsDuringHMBSupplementa7on

3studieshaveevaluatedHMBinrela;velyhealthyelderlyadults(>70years) Randomized,double-blindstudyinvolving31adults(men,15women,16)

70yearsofage1

Received3g/dayHMBorplacebofor8weeks Par;cipantsunderwentanexerciseprogram5day/week

2randomized,double-blindstudiesinvolving127elderlyadults(N=50,allwomenN=77,men38andwomen39) 2,3

Received2to3gHMB+1.5to2.25glysine+5to7.5garginineperdayorisocaloric,isonitrogenousplacebo

Studydura;onswere12weeks2and1year3 Noexercisecomponent

Generalfindingsfromthesestudies Someimprovementsinbodycomposi;on(leanmass,fatmass) Increasedproteinturnover Improvementinselectedmeasuresofstrengthandfunc;onaltests

ImprovementsdidnotalwaysoccurineitherplaceboorHMBgroup Indicatesthatthepar;cipantsmightnothavebeenabletodotheexercises

adequately

Benefitswerestrongerduringtheearlierperiodofthestudiesandtaperedtowardthestudyend

1. VukovichMD,etal.JNutr.2001131:2049-2052.2. FlakollP,etal.NutriKon.200420(5):445-451.3. BaierS,etal.JPENJParenterEnteralNutr.200933(1):71-82.

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HMBandWoundHealing

EffectsofHMBonbodycomposi;onandproteinturnoverledtoinves;ga;onsofHMBeffectsoncollagensynthesisandwoundhealing

Randomizedstudyinvolving35healthyadults(men,8women,27meanage,75years)

Crea;onofsmallwoundswithplas;ctubularinsertsthatwereplacedinthedeltoid Received14garginine+3gHMB+14gglutamineperday(n=18)oranisocaloric,

isonitrogenouscontrol(n=17)for2weeks

At2weeksposreatment Hydroxyprolineconcentra;on(surrogateforcollagenproduc;on)wasincreasedintheHMBgroupcomparedwiththecontrolgroup(72.2nmol/cmimplantvs43.2

nmol/cmimplantP

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p

HIV-InfectedPa7ents

Randomized,double-blindstudyinvolving43pa;entsinfectedwithHIVwhohaduninten;onalweightloss>5%overthe

previous3months

Received3gHMB+14gglutamine+14garginineperdayorplacebo(maltodextrin,isocaloric)for8weeks

WouldhavebeenbeertoalsohaveisonitrogenousplaceboOutcomevariables

Bodycomposi;onbyairdisplacementplethysmographyandskinfolds T-cellsubsets Changeinviralload

Resultsfollowonnextslide

ClarkRH,etal.JPENJParenterEnteralNutr.200024(3):133-139.45

OutcomesDuringSupplementa7onWithHMBand

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g pp

AminoAcidsinHIV-InfectedPa7ents

Bodycomposi;onimprovedinthesupplementa;ongroupcomparedwiththeplacebogroup Differencesweresignificantwithin8weeks

T-cellsubsets(CD3andCD5)werealsoincreasedsignificantlyinthesupplementa;ongroupcomparedwiththeplacebogroup

ViralloaddecreasedsignificantlywithHMB/Arg/Glutsupplementa;oncomparedwithplacebo

ReprintedwithpermissionfromClarkRH,etal.JPENJParenterEnteralNutr.200024(3):133-139.

aP=.009bP=.003

Placebo

HMB/Arg/Gln

5

4

-1

Cum

ulativeweightgain,kg

3

2

1

Start

0

4 weeks 8 weeks

a

PlaceboHMB/Arg/Gln

-1Cum

ulativeleangain,kg

3

2

1

Start

0

4 weeks 8 weeks

b

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OtherPosi7veHMBStudiesinCachec7c-Prone

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Popula7ons

Studieswith3gHMB+14gglutamine14garginineperday Randomized,double-blindstudyinvolving32pa;entswithsolidtumors

whohaduninten;onalweightloss>5%1

ReceivedHMB/arginine/glutamine,orisonitrogenous,isocaloricplacebofor24weeks

By4weeks,gainsinbodyweightandfat-freemasswereobservedinthesupplementa;ongroupcomparedwiththeplacebogroup

At23weeks,posi;veeffectsfromthesupplementa;onweremaintained Randomized,blindedstudyinvolving100cri;callyilltraumapa;ents2

ReceivedHMG,HMB/arginine/glutamine,orisonitrogenous,isocaloricplacebofor28days

Aer7daysofsupplementa;on Nitrogenreten;onwassignificantlyimprovedinthesupplementedgroupscompared

withtheplacebogroup(P=.05)

Urinary3-methylhis;dine(indicatorofmuscleproteolysis)wasunaffectedbysupplementa;on

1.MayPE,etal.AmJSurg.2002183(4):471-479.2. KuhlsDA,etal.JTrauma.200762(1):125-132.

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OtherPosi7veHMBStudiesinCachec7c-Prone

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Popula7ons

StudieswithHMBalone1,2 In34pa;entswithchronicobstruc;vepulmonarydiseasewhowererandomizedto

3g/dayHMBorcontrolfor7days,HMB-treatedpa;entshadimprovedindicatorsforinflamma;onandproteinbalancecomparedwiththecontrolgroup

In79bed-riddenelderlyadultswhowererandomizedto2g/dayHMBorcontrolfor14days,HMB-treatedadultshadreducedmuscleproteinbreakdowncomparedwith

thecontrolgroup

1.HsiehLC,etal.

AsiaPacJClinNutr.200615(4):544-550.2. HsiehLC,etal.AsiaPacJClinNutr.201019(2):200-208.

48

StudiesShowingNoEffectsofHMB/Arginine/Glutamine

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g g

Supplementa7on

Randomizedstudyinvolving40pa;entswithrheumatoidcachexia1 ReceivedHMB/arginine/glutamineorisocaloric,isonitrogenousplacebofor

12weeks

Similarimprovementsinbodycomposi;onandphysicalfunc;onwerereportedinbothgroups

Pa;entsreceivingsupplementa;onwerelesscachec;cvsotherstudies However,theMayPE,etal.studyhadhighdropoutrateduetoverysickpopula;on

Randomizedstudyinvolving30pa;entsundergoinglaparoscopicgastricbypasssurgery2 Received24gHMB/arginine/glutaminetwicedailyornosupplementa;on

post-opera;velyfor8weeks

Nodifferencesbetweengroupsinchangesofbodyweight,composi;on,orres;ngmetabolicrate

Noadverseeffectsonweightloss

1. MarcoraS,etal.ClinNutr.200524(3):442-454.2. ClementsRH,etal.SurgEndosc.201025(5):1376-1382.49

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50

HMB:Safety

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SafetyProfileofHMB:AnimalStudies

Variousanimalstudies(laboratoryandlivestockanimals)haveshownnoadverseeffectsevenathighdoses(upto4g/kg)1and

someposi;veeffects

Decreasedmortality(probablyduetoenhancedimmunity)2,3 Decreasedmuscleproteinbreakdown4 Improvedcarcassquality(morelean,lessfat)5

A90-daytoxicologystudyinratswithHMBat5%ofdiet(3.49g/kgformales,4.16g/kgforfemales)showedthatthisdosehadno

observedadverseeffects6

Thisincludedchangesinfoodconsump;onandbodyweight,aswellasclinicalchemistries,organweights,hematology,andmacro-andmicroscopic;ssueexamina;ons

1. PapetI,etal.BrJNutr.199777(6):885-896.2. NissenS,etal.PoultSci.199473(1):137-155.3. PetersonAL,etal.ImmunopharmImmunotox.199921(2):307-330.4. HolecekM,etal.FoodChemToxicol.200947(1):255-259.5.

VanKoeveringMT,etal.JAnimSci.199472(8):1927-1935.6. BaxterJH,etal.FoodChemToxicol.200543(12):1731-1741.

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SafetyProfileofHMB:HumanStudies

HMBhasbeenmarketedextensivelyasadietarysupplementsince1996withnopaernofadverseeventreports

Clinicalstudiesevalua;ngHMBorHMB+crea;nesupplementa;onforperiodsof3to8weekswithdosesupto6g/dayHMBhaveshown1-3 Noadversehematological,hepa;c,orrenaleffects Sometendencytodecreasetotalandlow-densitylipoprotein

cholesterol(5.8and7.3%,respec;vely)andreducesystolicbloodpressure(4.4mmHg)2

AlthoughHMBcanbeusedforcholesterolsynthesis,itappearsthatthecholesterolsynthesisislocalized(eg,muscle)anddoesnotadverselyaffectbloodcholesterollevels

Clinicalstudiesevalua;ngthecombina;onofHMB/Arginine/Glutamineinhealthyvolunteersandpa;entswithHIVorcancershowed4 Combina;onwassafe Improvementincertainhematologicalparameters

1. GallagherPM,etal.MedSciSportsExerc.200032(12):2116-2119.2. NissenS,etal.JNutr.2000130(8):1937-1945.3. CroweMJ,etal.IntJSportNutrExercMetab.200313(2):184-197.4. RathmacherJA,etal.JPENJParenterEnteralNutr.200428(2):65-75.

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Addi7onalInforma7onRegardingtheSafetyofHMB

NopublishedstudyhasreportedanyadverseeffectsofHMB However,someofthesestudiesdidnotreportadverseeventdataas

partofthedatapresented

ThereareverylimiteddatainhumansonHMBdosesupto6g/day

Notreatment-relatedadverseeventswerereportedMostHMBstudiesinhumanshavebeen8weeks

Therearesomedataoutto24weeksshowingsafetyDataonelderlyarelimited,butstudiesreviewedinthispresenta;oninbothhealthyandclinicalpopula;onshave

notreportedadverseevents

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HMBSummary

PrimarysourceofnaturalHMBiscatabolismoftheaminoacidleucine HMBs;mulatesmuscleproteinsynthesisandmayalso

Increasecellmembraneintegrityviacholesterolsynthesis Decreaseindicatorsofmuscledamage(crea;nekinaselevels) Beanan;catabolicagent

Clinicalresultsevalua;ngthebenefitsofHMBsupplementa;onaloneorwithothersupplementa;ononbodycomposi;onandstrengthhavebeen

mixed

Benefitsmaybereportedonceanop;malHMBdoseanddura;onthatcorrelateswithanathletessizeandtraininglevelisestablished

ClinicalresultssuggestthatHMBimproves Aerobicperformance Condi;onsassociatedwithlossofmusclemass Woundhealingcapacity

HMBhasbeenreportedtobesafeandwelltolerated Dataislimitedandfromshort-dura;onstudies

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