2Provide a general overview of HMB intake and metabolism Educational Objectives for the β-Hydroxy-β-Methylbutyrate (HMB) PresentationProvide a general overview of HMB intake and metabolismDescribe mechanistic studies of the roles of HMB in cell signaling pathways governing both muscle protein synthesis and degradationDiscuss role of HMB in reducing muscle damage during exerciseReview clinical data evaluating changes in body composition and performance in athletes receiving HMB supplementationUsed alone and in combination with creatine or other amino acidsIncluding effects in healthy, older adultsPresent other therapeutic and medical applicationsAddress the safety of HMB supplementation
3β-Hydroxy-β-Methylbutyrate (HMB) General overview of intake and metabolism
4Ca++ HO O– O –O OH What Is HMB? HMB is a leucine metabolite Leucine is an essential branched-chain amino acid that can trigger muscle protein synthesis and may inhibit protein degradation1Is it unknown whether leucine or its metabolites actively participate in protein synthesis/degradationLeucine is transaminated to α-ketoisocaproate (KIC) by branched-chain amino acid transferase, mainly in muscle tissuesApproximately 5% to 10% of α-ketoisocaproate (KIC) is converted to HMB (by KIC-dioxygenase) in the cell cytosolCalcium HMB has the following molecular structural formula2Ca++HOO–O–OOHNemet D, et al. IMAJ. 2005;7:Available at: Accessed May 10, 2011.
5Formation of HMB During Leucine Metabolism KICIsovaleryl-CoAβ-methyl-crotonyl-CoA(MC-CoA)β-hydroxy-β-methylbutyrate(HMB)HMB-CoAHMG-CoAMevalonateAcetyl-CoACholesterol(5-10% of Leu metabolism)Acetoacetyl-CoA(only when biotin is deficient)Adapted with permission from Nissen SL and Abumrad NN. J Nutr Biochem. 1997;8(6):
6Sources of HMB in the Diet Catabolism of leucineMean intake of leucine from food and supplements ( NHANES III) was 6.1 g/day1Assuming 5% to 10% conversion in the body, this represents 0.3 to 0.6 g HMB per dayTo get the 3-g HMB dose typically used in research, g leucine/day would have to be consumedHMB in foodsThere are traces of HMB in many animal- and plant-based foods, especially catfish and alfalfa2Institute of Medicine of the National Academies. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, DC: The National Academies Press; 2005:1008.Available at: Accessed May 10, 2011.
7HMB Absorption and Kinetics The mechanism of HMB absorption from the intestine has not been reportedIn 2 kinetic trials, plasma half-life was 2.5 hoursHMB levels return to baseline at ~ 9 hours after ingestionUp to 30% of an oral HMB dose is excreted unchanged in the urineThe addition of glucose to a calcium HMB supplement does not increase bioavailability or cellular uptake of HMBAdded glucose does slow HMB absorption through delayed gastric emptyingVukovich MD, et al. J Nutr Biochem. 2001;12(11):
8HMB BioavailabilityBioavailability of a free acid gel form was greater vs calcium HMB capsules2 studies, each with 8 healthy adults (4 male, 4 female)3 treatments1 g calcium HMB in capsule formEquivalent amount of HMB in free acid form in a gel (swallowed immediately)Free acid HMB gel held sublingually for 15 sec, then swallowedBlood and urinary HMB levels were monitored for 3 to 24 hours after ingestionOnly commercially available form is calcium saltcba30025020015010050400600800100012001400Time, minHMB, μmol/l plasmaCalcium HMB capsulesFree acid HMB gel conditionsa P < .05bP < .01cP < .0001Reprinted from Fuller JC Jr, et al. Br J Nutr. 2011;105:
9β-Hydroxy-β-Methylbutyrate (HMB) Mechanisms of action
10Possible HMB Mechanisms of Action HMB may be an anticatabolic agentStudies have documented potentially inhibited pathways such as the ubiquitin-proteasome pathway in a murine model1,2HMB may be a substrate for cholesterol synthesis in muscle3Formation of 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA, precursor for cholesterol synthesis)Muscle is dependent on cholesterol synthesis to meet its needsIncreased cell membrane integrity with improved muscle cholesterol synthesisStressed or injured muscle cells might not synthesize enough cholesterolHMB also helps to stimulate protein synthesis via the mTOR pathway4May be the real factor by which leucine stimulates protein synthesisHMB may have other effects (eg, immunomodulatory or hormonal)5Lecker SH, et al. J Nutr. 1999;129:227S-237S.Smith HJ, et al. Cancer Res. 2005;65:Nissen SL and Abumrad NN. J Nutr Biochem. 1997;8:Eley HL, et al. Am J Physiol Endocrinol Metab. 2008;295:E1409-E1416.Zanchi NE, et al. Amino Acids. 2011;40(4):
11The Ubiquitin-Proteasome Pathway for Protein Degradation Reprinted from Lecker SH, et al. J Nutr. 1999;129:227S-237S.
12Effects of HMB on the Ubiquitin-Proteasome Pathway Study performed in tumor-bearing (MAC16) mice that were treated for 3 days withOlive oil/phosphate-buffered saline (control)β-hydroxy-β-methylbutyrate (HMB)Eicosapentaenoic acid (EPA)HMB and EPAChymotrypsin-like enzyme activity (indicator of ubiquitin proteasome pathway) in the gastrocnemius muscle was assessed2018161412Fluorescent units/h/gram10aaa8642Control0.25 g/kg HMB0.6 g/kg EPAHMB + EPAa P < .005Reprinted from Smith HJ, et al. Cancer Res. 2005;65:
13Effects of HMB on Protein Synthesis and Degradation Initiator (PIF, LPS, TNF-, angiotensin II, etc.)XHMB blocks pathwayhereCaspase-8Caspase-3PKRNF- (nuclear accumulation)p38 MAPKROSPKR PProteasome + E3 mRNAeIF2 PeIF2Translational efficiencyProtein degradationProtein synthesisPIF, proteolysis-inducing factor; LPS, lipopolysaccharide; TNF, tumor necrosis factor; PKR, RNA-dependent protein kinase; MAPK, mitrogen-activated protein kinase; NF, nuclear factor; ROS, reactive oxygen species; eIF, eukaryotic initiation factor; P, phosphorylated.Based on Eley HL, et al. Am J Physiol Endocrinol Metab. 2008;295:E1417-E1426.
14Further Effects of HMB on Cellular Protein Synthesis HMB increases mTOR signaling pathway activitymTOR increases protein translationPromotes itKeeps it from being turned offEley HL, et al. Am J Physiol Endocrinol Metab. 2008;295:E1409-E1416.Adapted from SABiosciences, a QIAGEN company. Available at: Accessed June 27, 2011.
15Densitometry units, ph/tot Densitometry units, ph/tot Effects of HMB on Phosphorylation Status of mTOR Pathway Signaling FactorsHMB increased phosphorylation of mTOR signaling factors, stimulating protein synthesisHMB attenuates the depressive effects of proteolysis-inducing factor on protein synthesisp mTORTotal mTOR0.90.8a0.70.6Densitometry units, ph/tot0.50.40.30.20.1-2-12Time, hp P70S6KTotal P70S6K1.6b126.96.36.199Densitometry units, ph/tot0.80.60.40.2-2-12Time, hHMB (50 M) added here to murine myotubes.aDifferent from control, P < .05bDifferent from control, P < .01Abbreviations: mTOR, mammalian target of rapamycin; p, phosphorylation; P70S6k, 70-kDa ribosomal S6 kinase.Reprinted from Eley HL, et al. Am J Physiol Endocrinol Metab. 2007;293:E923-E931.
16β-Hydroxy-β-Methylbutyrate (HMB) HMB and indicators of muscle damage
17Exercise can result in muscle cell membrane disruption1,2 Evidence for a Protective Effect of HMB Against Muscle Cell Membrane DisruptionExercise can result in muscle cell membrane disruption1,2Elevations of creatine kinase (CK) and other enzyme (eg, lactate dehydrogenase [LDH]) levels in the blood can be indicators of muscle cell membrane disruption3,4Not necessarily muscle protein breakdownA few exercise studies have found a blunted CK response during HMB supplementation5,6McBride JM, et al. Med Sci Sports Exerc. 1998;30(1):67-72.Hurley BF, et al. Int J Sports Med. 1995;16(6):Cabaniss CD. In: Walker HK, Hall WD, Hurst JW, eds. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990: Chapter 32.Sarri E, et al. Biochem J. 2006;394(pt 1):Knitter AE, et al. J Appl Physiol. 2000;89:van Someren KA, et al. Int J Sport Nutr Exerc Metab. 2005;15(4):
18Effect of HMB Supplementation on Creatine Kinase Levels During Exercise Study involving 13 participants (5 male, 8 female) that had a history of running at least 48 km/wkParticipants received 3 g HMB or placebo daily for 6 weeks before a prolonged run (double-blind)Pair-matched based on best 2-mile run timeThe run was 20 km on a collegiate cross-country courseCK and LDH were measured 2 weeks before the run (Pre), immediately after the run (Post), and at 1, 2, 3, and 4 days after the runResults follow on next slideKnitter AE, et al. J Appl Physiol. 2000;89:
19Time relative to the prolonged run Effect of HMB Supplementation on Creatine Kinase Levels During Exercise (Cont’d)Main effect for treatment in CK measurement, P = .05, with no significant group × time interactionA significant main effect for treatment in LDH measurement (P = .003), with no significant group × time interaction450PlaceboHMB400350300250CPK activity, U/L20015010050PrePost1dPost2dPost3dPost4dPostTime relative to the prolonged runReprinted from Knitter AE, et al. J Appl Physiol. 2000;89:
20Effects of HMB Supplementation on Muscle Damage During Exercise 1 study showed positive effects of 3 g HMB and 0.3 g KIC/day versus placebo when received for 2 weeks prior to exercise (biceps curl with prolonged eccentric phase)1In 6 nonresistance-trained male subjectsSupplementation reduced the delayed onset of muscle soreness (DOMS) ratings (P < .05)Blunted CK response and decrement of 1-repetition maximumSeveral studies did not show any effects of HMB on muscle damage2-5However, a major difference between the positive HMB studies and the studies without any effect is the length of supplementationRanged from a single acute HMB administration (3 g) before or after exercise to 11 days of supplementation (3 g/day) before exerciseIn addition, 1 study showing no effects of HMB/KIC supplementation on muscle damage involved intensive exercise (40 minutes of downhill running)4Any supplementation may not reduce that level of muscle damageAlthough not significant, a trend was observed toward more rapid recovery of muscle function with HMB/KIC supplementationvan Someren KA, et al. Int J Sport Nutr Exerc Metab. 2005;15(4):Wilson JM, et al. Nutr Metab (Lond). 2009;6:6. DOI: /Paddon-Jones D, et al. Int J Sport Nutr Exerc Metab. 2001;11(4):Nunan D, et al. J Strength Cond Res. 2010;24(2):Hoffman JR, et al. J Strength Cond Res. 2004;18(4):
21β-Hydroxy-β-Methylbutyrate (HMB) Effects of HMB on body composition and strength
22Historical Background on HMB Supplementation Numerous studies of HMB supplementation in several animal models (steers, lambs, rats, chickens, trout, and horses) showed positive effects onCarcass quality, protein metabolism, immune response, muscle damage, antioxidant status, and blood lipid profileDr. Steve Nissen (Animal Science, Iowa State University) is essentially the “father” of the HMB storyPerformed initial human studies of HMB supplementation in the 1990s1Also performed a meta-analysis of supplementation studies in 2003 with respect to effects on lean body mass and strength gains2Nissen S, et al. J Appl Physiol. 1996;81(5):Nissen SL and Sharp RL. J Appl Physiol. 2003;94:
23Change in total body strength, kg Change in Overall Muscle Strength During HMB Supplementation: Initial Study41 healthy young adults (19-29 years), untrained2 protein levels: 117 g/day (control) or 175 g/dayDiet was controlled, nutrient powder in a shake3 HMB supplementation doses randomized and blinded within each protein group0, 1.5, or 3.0 g/dayMixed in orange juiceWeight training for 1.5 hours 3 days/week for 3 weeksData from control and high protein groups were pooled because there was no difference in HMB resultsOverall muscle strength increased at 3 weeks8% in control group13% in 1.5 g HMB group18% in 3.0 g HMB group800Control1.5 g HMB3.0 g HMBbb600c400Change in total body strength, kga200-200Week 1Week 3aP < .03bP < .02cP < .01Reprinted from Nissen S, et al. J Appl Physiol. 1996;81(5):
24% Change in 3-MH from basal Change in Urinary 3-Methylhistidine (3-MH) Excretion During HMB Supplementation: Initial Study3-MH is a muscle-specific amino acidFormed during breakdown of muscle proteins (actin and myosin)Excreted unchanged in urineHMB supplementation reduced the physiologic increase in 3-MH during exerciseTotal muscle breakdown per day increased from 3% at baseline to6% at week 3 in control group5.5% at week 3 in 1.5 g HMB group4.5% at week 3 in 3.0 g HMB group100Control1.5 g HMB3.0 g HMB80a60% Change in 3-MH from basal40b20aP < .04bP < .001-20Week 1Week 2Week 3Reprinted from Nissen S, et al. J Appl Physiol. 1996;81(5):Elia M, et al. Br Med J. 1981;282:
25Change in Fat-Free Mass During HMB Supplementation: Study 2 32 healthy adults (19-22 years; mean body weight, 99 kg), almost all engaged in an exercise program before study entry and ate at university training tableRandomized to placebo or 3 g HMB per day for 7 weeksHMB provided in a nutrient/protein powder; placebo was isocaloric orange juiceParticipants ate normal diet (no strict dietary control)Daily protein intake was estimated at 200 g (HMB) vs 180 g (placebo)Participants lifted weights 2 to 3 hours/day, 6 days/weekTotal body electrical conductivity (TOBEC) was used for body composition analysisHMB supplementation increased fat-free mass early in exercise regimen compared with placeboSignificant gains continued through day 39aaa3.50a2.501.50Fat-free mass gain, kg0.50-0.50PlaceboHMB + nutrient powder-1.501020304050Day of studyaP < .05Reprinted from Nissen S, et al. J Appl Physiol. 1996;81(5):
26Positive Effects of HMB Supplementation on Strength, Power, and/or Body Composition Study DesignTreatmentTrainingResultsDouble-blind in untrained college men, N = 3710, 38, or 76 mg/kg/day HMB (equivalent to 0, 3, or 6 g/day) for 8 wksResistance, 3 times/wk (80% 1-RM) assessed every 2 wksCompared with other 2 groups,Fat-free mass increased in the 38 mg/kg dose group (P < .05 for both)Peak isometric torque (knee extensor) increase in 38 mg/kg dose group (P < .05)Plasma creatine kinase (CK) 48 hours after exercise was higher in 0 mg/kg (P < .05)No difference between the 38 and 76 mg/kg dose groupsRandomized in trained or untrained adults (men, 39; women, 36; age, year), N = 7523 g/day HMB or placebo for 4 wksStrength, 3 times/wk (90% 1-RM)Compared with placebo group, the HMB group hadGreater increase in upper body strength (P = .008)Blunted postexercise rise in creatine kinase vs placeboSomewhat greater increase in fat-free mass (P = 0.08)Randomized, double-blind in resistance-trained men (young adults), N = 2233 g/day HMB or placebo for 9 wksStrength, 3 times/wk(1-RM)Significantly increased leg extension strength (~14% vs ~5% for placebo; P = .05)Similar upper body strength (bench press, biceps curls)Small, but positive, changes in body compositionRandomized, double-blind in elite, national-team level, adolescent volleyball players (men, 14; women, 14), N = 2843 g/day HMB or placebo for first 7 wks of the training seasonVolleyball skills (20%), power and speed drills (25%), interval (25%), endurance (15%) and resistance (circuit-style; 15%), hr/wkIncreased bench press and leg press strength (6-RM; P < .05)Increased peak and mean anaerobic power (Wingate test; P < .01)Increased some measures of knee flexion isokinetic forceNo effects of HMB on aerobic capacity or anabolic and catabolic hormonesAbbreviations: RM, repetition maximum. 1. Gallagher PM, et al. Med Sci Sports Exerc. 2000;32(12): Panton LB, et al. Nutrition. 2000;16(9): Thomson JS, et al. J Strength Cond Res. 2009;23(3): Portal S, et al. Eur J Appl Physiol. 2011;Feb 16:E-pub.26
27Studies Showing No Effects of HMB Supplementation on Strength and Body Composition Study DesignTreatmentTrainingResultsRandomized, double-blind in experienced (5.5 years), resistance-trained athletes, N = 4010, 3, or 6 g/day HMB for 28 days in a carbohydrate/protein powderMaintained individualized resistance training program (~7 hrs/wk) and kept training logsNeither dose of HMB influencedStrength (1-RM)Body composition (by dual energy X-ray absorptiometer)Body anabolic/catabolic statusBlood chemistriesRandomized, double-blind in national-level athletes (polo, 17; rowers, 10) with ≥ 2 years of resistance training, N = 2723 g/day HMB (timed-release or standard capsule) or placebo for 6 wksResistance, 2-3 times/wk (Pre-competition phase of training)StrengthBody compositionCreatine kinase levelsTrend toward higher creatine kinase level in placebo group (P = .07 for group x time interaction)Randomized, crossover in collegiate football players, N = 3533 g/day HMB or placebo for 4 wks (16 players got HMB first, 19 got placebo first)Intensive resistance, 20 hrs/wk and various other typesNo changes in body composition or strength for either placebo or HMB groupsLack of change in placebo group suggests overtrainingRandomized, single-blind in collegiate football players, N = 2643 g/day HMB or placebo for 10 daysPreseason training campNo changes between baseline and post training in either placebo or HMB groups for anaerobic powerNo changes between placebo and HMB groups for changes in creatine kinase, myoglobin, testosterone, or cortisol levelsAbbreviations: RM, repetition maximum. 1. Kreider RB, et al. Int J Sports Med. 1999;20(8): Slater G, et al. Int J Sport Nutr Exerc Metab. 2001;11(3): Ransone J, et al. J Strength Cond Res. 2003;17(1): Hoffman JR, et al. J Strength Cond Res. 2004;18(4):
28Why the Discrepancy in HMB Studies? There are potential differences in muscle metabolism between more highly trained and untrained athletesMore potential for benefit probably in untrained athletesLength of HMB supplementation may have been insufficient in negative studiesMore highly trained athletes might require longer supplementation (only 1 negative study > 4 weeks duration)Very limited data (only 2 studies) on HMB doses over 3 g/dayLarger body size might require a larger doseType of training may be importantDifferences between laboratoriesThere are several good meta-analyses and reviews of HMB and athletic performance1-6Portal S, et al. J Ped Endocrinol Metab. 2010;23(7):Zanchi NE, et al. Amino Acids. 2011;40(4):Alon T, et al. Res Comm Mol Pathol Pharmacol. 2002;111(1-4):Nissen SL and Sharp RL. J Appl Physiol. 2003;94:Rowlands DS and Thomson JS. J Strength Cond Res. 2009;23(3):Wilson GJ, et al. Nutr Metab. 2008;5:1 DOI: /
29Counterfeit HMB?The initial human research on HMB came from Steve Nissen’s laboratory at Iowa StateThe compound they studied and the one in their associated patents calcium -hydroxy--methylbutyrateA product marketed in the UK (HMB-1000, Maximuscle Ltd.) has been shown in one study to be ineffective at reducing exercise-induced muscle damage1Subsequent analysis of the HMB-1000 product revealed that it actually contained no HMB2It contains a related leucine metabolite (calcium hydroxy-methylbutyrate)This raises the potential issue that some “no effect” studies with HMB could be due to use of a product that does not contain HMB, but rather similar compounds that might not have the same biological activity1Nunan et al. J Strength Cond Res 2010;24:2Abumrad NN, Rathmacher JA. J Strength Cond Res 2011:25(7):1-2.
30β-Hydroxy-β-Methylbutyrate (HMB) HMB and aerobic performance
31HMB and Measures of Aerobic Capacity Most of the research regarding HMB has focused on strength and body compositionAbility to train harder with less muscle breakdown from exercise may be a mechanism through which HMB could facilitate aerobic performance2 studies have evaluated aerobic capacity during HMB supplementation1,2In these studies, the mechanism of how HMB might work is not clearVukovich MD and Dreifort GD. J Strength Cond Res. 2001;15(4):Lamboley CR, et al. Int J Sport Nutr Exerc Metab. 2007;17(1):56-69.
32Measures of Aerobic Capacity: Study 1 Randomized, double-blind, crossover study involving 8 endurance-trained cyclistsReceived 3 g/day HMB, leucine, or placebo for three 2-week supplementation periods, with 2-week washout periods in betweenParticipants performed graded cycle ergometry testsVO2peak, VO2max , and lactate accumulation peak were similar between all groupsOnset of blood lactate accumulation (VO2 at blood lactate level of 2 mM) was increased in both the HMB and leucine groups compared with the placebo group (9.1%, 2.1%, and 0.8%, respectively)Leucine had no other notable effects on aerobic parametersLactate threshold (% VO2max) , and time to reach VO2peak were also increased in the HMB group compared with the leucine and placebo groupsBlood HMB levels were much lower (40- to 60-fold) in the leucine group versus the HMB groupSupports previous data on low conversion rates of leucine to HMBVukovich MD and Dreifort GD. J Strength Cond Res. 2001;15(4):
33Measures of Aerobic Capacity: Study 2 Randomized study involving 16 college studentsReceived 3 g/day HMB or placebo for 5 weeksStudents performed interval training 3 times/week on a treadmillCompared with the placebo group at 5 weeks, the HMB group hadIncreased VO2max (13.4% vs 8.4% for placebo; P < .05)Increased respiratory compensation pointDecreased time to exhaustion at maximal oxygen consumption (Tmax)This was largely a function of the greater increase in VO2maxThe larger the VO2max, the tougher it is to run at that intensityLamboley CR, et al. Int J Sport Nutr Exerc Metab. 2007;17(1):56-69.
34β-Hydroxy-β-Methylbutyrate (HMB) HMB studies with creatine or with amino acids
35HMB in Combination With Creatine A natural question is whether synergistic or additive effects will occur during simultaneous supplementation with creatine and HMBClinical data have reported mixed resultsRandomized, double-blind study involving 40 volunteersReceived 3 g/day HMB, 20 g/day for 7 days followed by 10 g/day for 14 days creatine (Cr), creatine plus HMB (CrHMB), or placebo for 3 weeksVolunteers performed progressive resistance trainingLean body mass gains (assessed via bioelectric impedance) were 0.92 kg, 0.39 kg, and 1.54 kg greater for Cr, HMB, and CrHMB groups, respectively compared with placeboSignificant main effect for Cr group (P = .05), and a trend for HMB group (P = .08)Data were additive, no Cr × HMB interaction (P = .73)Similar results were reported for strength gains, with additive effects for Cr and HMBReduction in exercise-induced creatine phosphokinase levels was greatest in the HMB group (main effect, P = .01)Addition of creatine antagonized the HMB effect (P = .04 for Cr × HMB interaction)Jówko E, et al. Nutrition. 2001;17(7-8):
36HMB in Combination With Creatine Randomized study in basketball players1Received creatine, HMB, creatine and HMB, or placebo for 30 daysDoses were not specifiedPlayers in the combination group had increased maximum power and total work output compared with the other groupsNo additional increase in lactate or fall in muscle pH2 studies did not show benefits of the creatine/HMB combination2,3Both studies were in 57 elite rugby players (N = 30; N = 27)Received 3 g/day HMB, 3 g/day creatine, creatine and HMB, or placebo for 6 weeksNo benefits were observed onMuscular strength and enduranceLeg powerAnthropometryAerobic abilityAnaerobic abilityZajac A, et al. J Hum Kinet. 2003;10:O’Connor DM and Crowe MJ. J Strength Cond Res. 2007;21(2):O’Connor DM and Crowe MJ. J Sports Med Phys Fitness. 2003;43(1):64-68.
37HMB in Combination With the Amino Acids Arginine, Glutamine, and Taurine Randomized, double-blind study involving 17 healthy men who were recreationally active (no resistance training in previous 6 months)Received HMB plus amino acids (MA) or an isonitrogenous control twice daily for 12 weeksMA formula = 1.5 g HMB, 7 g glutamine, 7 g arginine, 3 g taurine, 5.8 g dextroseControl = 10 g glycine, 11.5 g alanine, 1.5 g glutamate, 1.5 g serineVolunteers performed resistance training 3 times/week (10 exercises for whole body)One light (12- to 14-repetition maximum [RM]), 1 moderate (8- to 10-RM), and 1 heavy (3- to 5-RM) day each weekOutcome variablesStrength (1-RM)Vertical jump powerHormonal and muscle damage responses to an acute bout of resistance trainingBody composition and circumferencesTendon sizeResults follow on next slidesKraemer WJ, et al. Med Sci Sports Exerc. 2009;41(5):
38Body Composition Changes During Supplementation With HMB and Amino Acids Body mass and lean body mass continuously increased in both groupsBody fat continuously decreased in both groupsAfter 12 weeks of training, the supplementation group had significantly improved body compositionABCCONMACONMACONMA9580a,b32a,b759030a2870aa8526Body mass, kgLean body mass, kg65Body fat, %a,b2480226020755518167050V1V5V8V1V5V8V1V5V8Time pointTime pointTime pointaSignificant difference from V1, P .05bSignificant difference from control, P .05Abbreviations: V1, before training; V5, after 6 wks; V8, after 12 wks.Kraemer WJ, et al. Med Sci Sports Exerc. 2009;41(5):
39Strength and Power Changes During Supplementation With HMB and Amino Acids Both muscle strength and power continuously increased in both groupsAfter 6 weeks of training, the supplementation group had significantly improved muscle strength that remained enhanced at the 12-week assessmentAt 12 weeks, the supplementation group had significantly improved muscle powerABCCONMACONMACONMAa,ba,b6000120a,ba140a,ba,ba55001005000aa120Squat, kgBench, kgVertical jump power, w4500804000100350060803000V1V5V8V1V5V8V1V5V8Time pointTime pointTime pointaSignificant difference from V1, P .05bSignificant difference from control, P .05Abbreviations: V1, before training; V5, after 6 wks; V8, after 12 wks.Kraemer WJ, et al. Med Sci Sports Exerc. 2009;41(5):
40Changes in Hormone Levels and Indicators of Muscle Damage During Supplementation With HMB and Amino AcidsCompared with the placebo group, the supplementation group hadIncreased resting and exercise-induced testosterone levelsIncrease resting growth hormone concentrationsReduced pre-exercise cortisol concentrationsAttenuated circulating creatine kinase and malondialdehyde concentrationsIndicative of less muscle damageIn general, the effects from supplementation on creatine kinase, malondialdehyde, and cortisol were more pronounced at the 12-week point in the studyNo dietary intake data were reported for the studyKraemer WJ, et al. Med Sci Sports Exerc. 2009;41(5):
41β-Hydroxy-β-Methylbutyrate (HMB) HMB in the elderly and therapeutic/medical applications
42HMB in the ElderlyThere are a number of nutritional problems in the elderly population for which there may be applications for HMBSarcopenia due to aging and inactivity1BedrestInability to perform exercise that can help maintain muscle massWound healing (eg, decubiti)2Presence of disease states (eg, cancer, congestive heart failure) associated with significant cachexia3,4Generalized malnutrition5HMB has been studied in both healthy elderly and those with various conditions associated with loss of muscle mass and wound healing capacityBaier S, et al. JPEN J Parenter Enteral Nutr 2009;33(1):71-82.Williams JZ, et al. Ann Surg. 2002;236(3):Hsieh LC, et al. Asia Pac J Clin Nutr. 2006;15(4):May PE, et al. Am J Surg. 2002;183(4):Hsieh LC, et al. Asia Pac J Clin Nutr. 2010;19(2):
43Body Composition and Protein Metabolism in Healthy Older Adults During HMB Supplementation 3 studies have evaluated HMB in relatively healthy elderly adults (> 70 years)Randomized, double-blind study involving 31 adults (men, 15; women, 16) 70 years of age1Received 3 g/day HMB or placebo for 8 weeksParticipants underwent an exercise program 5 day/week2 randomized, double-blind studies involving 127 elderly adults (N = 50, all women; N = 77, men 38 and women 39)2,3Received 2 to 3 g HMB to 2.25 g lysine + 5 to 7.5 g arginine per day or isocaloric, isonitrogenous placeboStudy durations were 12 weeks2 and 1 year3No exercise componentGeneral findings from these studiesSome improvements in body composition (lean mass, fat mass)Increased protein turnoverImprovement in selected measures of strength and functional testsImprovements did not always occur in either placebo or HMB groupIndicates that the participants might not have been able to do the exercises adequatelyBenefits were stronger during the earlier period of the studies and tapered toward the study endVukovich MD, et al. J Nutr. 2001;131:Flakoll P, et al. Nutrition. 2004;20(5):Baier S, et al. JPEN J Parenter Enteral Nutr. 2009;33(1):71-82.
44HMB and Wound HealingEffects of HMB on body composition and protein turnover led to investigations of HMB effects on collagen synthesis and wound healingRandomized study involving 35 healthy adults (men, 8; women, 27; mean age, 75 years)Creation of small wounds with plastic tubular inserts that were placed in the deltoidReceived 14 g arginine + 3 g HMB + 14 g glutamine per day (n = 18) or an isocaloric, isonitrogenous control (n = 17) for 2 weeksAt 2 weeks posttreatmentHydroxyproline concentration (surrogate for collagen production) was increased in the HMB group compared with the control group (72.2 nmol/cm implant vs 43.2 nmol/cm implant; P < .03)Total protein accumulation was similar between groupsTotal α-amino nitrogen (surrogate for total wound protein synthesis) was also similar between groupsHowever, baseline characteristics of the 2 groups were not presentedComparable baseline wound healing is not establishedWilliams JZ, et al. Ann Surg. 2002;236(3):
45HMB and Cachetic-Prone Populations: HIV-Infected Patients Randomized, double-blind study involving 43 patients infected with HIV who had unintentional weight loss > 5% over the previous 3 monthsReceived 3 g HMB + 14 g glutamine + 14 g arginine per day or placebo (maltodextrin, isocaloric) for 8 weeksWould have been better to also have isonitrogenous placeboOutcome variablesBody composition by air displacement plethysmography and skinfoldsT-cell subsetsChange in viral loadResults follow on next slideClark RH, et al. JPEN J Parenter Enteral Nutr. 2000;24(3):
46Cumulative weight gain, kg Cumulative lean gain, kg Outcomes During Supplementation With HMB and Amino Acids in HIV-Infected PatientsBody composition improved in the supplementation group compared with the placebo groupDifferences were significant within 8 weeksT-cell subsets (CD3 and CD5) were also increased significantly in the supplementation group compared with the placebo groupViral load decreased significantly with HMB/Arg/Glut supplementation compared with placebo5PlaceboHMB/Arg/Gln3bPlaceboHMB/Arg/Gln423aCumulative weight gain, kg21Cumulative lean gain, kg1-1-1Start4 weeks8 weeksStart4 weeks8 weeksaP = .009bP = .003Reprinted with permission from Clark RH, et al. JPEN J Parenter Enteral Nutr. 2000;24(3):
47Other Positive HMB Studies in Cachectic-Prone Populations Studies with 3 g HMB + 14 g glutamine 14 g arginine per dayRandomized, double-blind study involving 32 patients with solid tumors who had unintentional weight loss > 5%1Received HMB/arginine/glutamine, or isonitrogenous, isocaloric placebo for 24 weeksBy 4 weeks, gains in body weight and fat-free mass were observed in the supplementation group compared with the placebo groupAt 23 weeks, positive effects from the supplementation were maintainedRandomized, blinded study involving 100 critically ill trauma patients2Received HMG, HMB/arginine/glutamine, or isonitrogenous, isocaloric placebo for 28 daysAfter 7 days of supplementationNitrogen retention was significantly improved in the supplemented groups compared with the placebo group (P = .05)Urinary 3-methylhistidine (indicator of muscle proteolysis) was unaffected by supplementationMay PE, et al. Am J Surg. 2002;183(4):Kuhls DA, et al. J Trauma. 2007;62(1):
48Other Positive HMB Studies in Cachectic-Prone Populations Studies with HMB alone1,2In 34 patients with chronic obstructive pulmonary disease who were randomized to 3 g/day HMB or control for 7 days, HMB-treated patients had improved indicators for inflammation and protein balance compared with the control groupIn 79 bed-ridden elderly adults who were randomized to 2 g/day HMB or control for 14 days, HMB-treated adults had reduced muscle protein breakdown compared with the control groupHsieh LC, et al. Asia Pac J Clin Nutr. 2006;15(4):Hsieh LC, et al. Asia Pac J Clin Nutr. 2010;19(2):
49Studies Showing No Effects of HMB/Arginine/Glutamine Supplementation Randomized study involving 40 patients with rheumatoid cachexia1Received HMB/arginine/glutamine or isocaloric, isonitrogenous placebo for 12 weeksSimilar improvements in body composition and physical function were reported in both groupsPatients receiving supplementation were less cachectic vs other studiesHowever, the May PE, et al. study had high dropout rate due to very sick populationRandomized study involving 30 patients undergoing laparoscopic gastric bypass surgery2Received 24 g HMB/arginine/glutamine twice daily or no supplementation post-operatively for 8 weeksNo differences between groups in changes of body weight, composition, or resting metabolic rateNo adverse effects on weight lossMarcora S, et al. Clin Nutr. 2005;24(3):Clements RH, et al. Surg Endosc. 2010;25(5):
51Safety Profile of HMB: Animal Studies Various animal studies (laboratory and livestock animals) have shown no adverse effects even at high doses (up to 4 g/kg)1 and some positive effectsDecreased mortality (probably due to enhanced immunity)2,3Decreased muscle protein breakdown4Improved carcass quality (more lean, less fat)5A 90-day toxicology study in rats with HMB at 5% of diet (3.49 g/kg for males, 4.16 g/kg for females) showed that this dose had no observed adverse effects6This included changes in food consumption and body weight, as well as clinical chemistries, organ weights, hematology, and macro- and microscopic tissue examinationsPapet I, et al. Br J Nutr. 1997;77(6):Nissen S, et al. Poult Sci. 1994;73(1):Peterson AL, et al. Immunopharm Immunotox. 1999;21(2):Holecek M, et al. Food Chem Toxicol. 2009;47(1):Van Koevering MT, et al. J Anim Sci. 1994;72(8):Baxter JH, et al. Food Chem Toxicol. 2005;43(12):
52Safety Profile of HMB: Human Studies HMB has been marketed extensively as a dietary supplement since 1996 with no pattern of adverse event reportsClinical studies evaluating HMB or HMB + creatine supplementation for periods of 3 to 8 weeks with doses up to 6 g/day HMB have shown1-3No adverse hematological, hepatic, or renal effectsSome tendency to decrease total and low-density lipoprotein cholesterol (–5.8 and –7.3%, respectively) and reduce systolic blood pressure (–4.4 mm Hg)2Although HMB can be used for cholesterol synthesis, it appears that the cholesterol synthesis is localized (eg, muscle) and does not adversely affect blood cholesterol levelsClinical studies evaluating the combination of HMB/Arginine/Glutamine in healthy volunteers and patients with HIV or cancer showed4Combination was safeImprovement in certain hematological parametersGallagher PM, et al. Med Sci Sports Exerc. 2000;32(12):Nissen S, et al. J Nutr. 2000;130(8):Crowe MJ, et al. Int J Sport Nutr Exerc Metab. 2003;13(2):Rathmacher JA, et al. JPEN J Parenter Enteral Nutr. 2004;28(2):65-75.
53Additional Information Regarding the Safety of HMB No published study has reported any adverse effects of HMBHowever, some of these studies did not report adverse event data as part of the data presentedThere are very limited data in humans on HMB doses up to 6 g/dayNo treatment-related adverse events were reportedMost HMB studies in humans have been ≤ 8 weeksThere are some data out to 24 weeks showing safetyData on elderly are limited, but studies reviewed in this presentation in both healthy and clinical populations have not reported adverse events
54HMB Summary HMB has been reported to be safe and well tolerated Primary source of natural HMB is catabolism of the amino acid leucineHMB stimulates muscle protein synthesis and may alsoIncrease cell membrane integrity via cholesterol synthesisDecrease indicators of muscle damage (creatine kinase levels)Be an anticatabolic agentClinical results evaluating the benefits of HMB supplementation alone or with other supplementation on body composition and strength have been mixedBenefits may be reported once an optimal HMB dose and duration that correlates with an athletes size and training level is establishedClinical results suggest that HMB improvesAerobic performanceConditions associated with loss of muscle massWound healing capacityHMB has been reported to be safe and well toleratedData is limited and from short-duration studies