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β -Hydroxy- β -Methylbutyrate (HMB)

β -Hydroxy- β -Methylbutyrate (HMB). Educational Objectives for the β -Hydroxy- β -Methylbutyrate (HMB) Presentation. Provide a general overview of HMB intake and metabolism

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β -Hydroxy- β -Methylbutyrate (HMB)

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  1. β-Hydroxy-β-Methylbutyrate (HMB)

  2. Educational Objectives for the β-Hydroxy-β-Methylbutyrate (HMB) Presentation • Provide a general overview of HMB intake and metabolism • Describe mechanistic studies of the roles of HMB in cell signaling pathways governing both muscle protein synthesis and degradation • Discuss role of HMB in reducing muscle damage during exercise • Review clinical data evaluating changes in body composition and performance in athletes receiving HMB supplementation • Used alone and in combination with creatine or other amino acids • Including effects in healthy, older adults • Present other therapeutic and medical applications • Address the safety of HMB supplementation

  3. β-Hydroxy-β-Methylbutyrate (HMB) General overview of intake and metabolism

  4. 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 degradation1 • Is it unknown whether leucine or its metabolites actively participate in protein synthesis/degradation • Leucine is transaminated to α-ketoisocaproate (KIC) by branched-chain amino acid transferase, mainly in muscle tissues • Approximately 5% to 10% of α-ketoisocaproate (KIC) is converted to HMB (by KIC-dioxygenase) in the cell cytosol • Calcium HMB has the following molecular structural formula2 OH –O HO O– Ca++ O O • Nemet D, et al. IMAJ. 2005;7:328-332. • Available at: www.chemblink.com/products/135236-72-5.htm. Accessed May 10, 2011.

  5. Formation of HMB During Leucine Metabolism Leucine Isovaleryl-CoA KIC (5-10% of Leu metabolism) (only whenbiotin is deficient) β-hydroxy-β-methylbutyrate (HMB) β-methyl-crotonyl-CoA (MC-CoA) HMB-CoA HMG-CoA Mevalonate Acetoacetyl-CoA Acetyl-CoA Cholesterol Adapted with permission from Nissen SL and Abumrad NN. J Nutr Biochem. 1997;8(6):300-311.

  6. Sources of HMB in the Diet • Catabolism of leucine • Mean intake of leucine from food and supplements (1988-1994 NHANES III) was 6.1 g/day1 • Assuming 5% to 10% conversion in the body, this represents 0.3 to 0.6 g HMB per day • To get the 3-g HMB dose typically used in research, 30-60 g leucine/day would have to be consumed • HMB in foods • There are traces of HMB in many animal- and plant-based foods, especially catfish and alfalfa2 • Institute 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: http://www.webmd.com/heart-disease/news/20000818/researchers-take-closer-look-at-supplement-sensation. Accessed May 10, 2011.

  7. HMB Absorption and Kinetics • The mechanism of HMB absorption from the intestine has not been reported • In 2 kinetic trials, plasma half-life was 2.5 hours • HMB levels return to baseline at ~ 9 hours after ingestion • Up to 30% of an oral HMB dose is excreted unchanged in the urine • The addition of glucose to a calcium HMB supplement does not increase bioavailability or cellular uptake of HMB • Added glucose does slow HMB absorption through delayed gastric emptying Vukovich MD, et al. J Nutr Biochem. 2001;12(11):631-639.

  8. HMB Bioavailability • Bioavailability of a free acid gel form was greater vs calcium HMB capsules • 2 studies, each with 8 healthy adults (4 male, 4 female) • 3 treatments • 1 g calcium HMB in capsule form • Equivalent amount of HMB in free acid form in a gel (swallowed immediately) • Free acid HMB gel held sublingually for 15 sec, then swallowed • Blood and urinary HMB levels were monitored for 3 to 24 hours after ingestion • Only commercially available form is calcium salt 300 250 c c c 200 Free acid HMB gel conditions c HMB, μmol/l plasma 150 c 100 Calcium HMB capsules a b 50 a a 0 aP < .05 bP < .01 cP < .0001 0 200 400 600 800 1000 1200 1400 Time, min Reprinted from Fuller JC Jr, et al. Br J Nutr. 2011;105:367-372.

  9. β-Hydroxy-β-Methylbutyrate (HMB) Mechanisms of action

  10. Possible HMB Mechanisms of Action • HMB may be an anticatabolic agent • Studies have documented potentially inhibited pathways such as the ubiquitin-proteasome pathway in a murine model1,2 • HMB may be a substrate for cholesterol synthesis in muscle3 • Formation of 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA, precursor for cholesterol synthesis) • Muscle is dependent on cholesterol synthesis to meet its needs • Increased cell membrane integrity with improved muscle cholesterol synthesis • Stressed or injured muscle cells might not synthesize enough cholesterol • HMB also helps to stimulate protein synthesis via the mTOR pathway4 • May be the real factor by which leucine stimulates protein synthesis • HMB may have other effects (eg, immunomodulatory or hormonal)5 • Lecker SH, et al. J Nutr. 1999;129:227S-237S. • Smith HJ, et al. Cancer Res. 2005;65:277-283. • Nissen SL and Abumrad NN. JNutr Biochem. 1997;8:300-311. • Eley HL, et al. Am J Physiol Endocrinol Metab. 2008;295:E1409-E1416. • Zanchi NE, et al. Amino Acids. 2011;40(4):1015-1025.

  11. The Ubiquitin-Proteasome Pathway for Protein Degradation Reprinted from Lecker SH, et al. J Nutr. 1999;129:227S-237S.

  12. Effects of HMB on the Ubiquitin-Proteasome Pathway • Study performed in tumor-bearing (MAC16) mice that were treated for 3 days with • Olive oil/phosphate-buffered saline (control) • β-hydroxy-β-methylbutyrate (HMB) • Eicosapentaenoic acid (EPA) • HMB and EPA • Chymotrypsin-like enzyme activity (indicator of ubiquitin proteasome pathway) in the gastrocnemius muscle was assessed 20 18 16 14 12 10 Fluorescent units/h/gram a a a 8 6 4 2 0 Control 0.25 g/kg HMB 0.6 g/kg EPA HMB + EPA aP < .005 Reprinted from Smith HJ, et al. Cancer Res. 2005;65:277-283.

  13. Effects of HMB on Protein Synthesis and Degradation Initiator (PIF, LPS, TNF-, angiotensin II, etc.) X HMB blocks pathway here Caspase-8 Caspase-3 PKR NF- (nuclear accumulation) p38 MAPK ROS PKR P Proteasome + E3 mRNA eIF2 P eIF2 Translational efficiency Protein degradation Protein synthesis PIF, 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.

  14. Further Effects of HMB on Cellular Protein Synthesis • HMB increases mTOR signaling pathway activity • mTOR increases protein translation • Promotes it • Keeps it from being turned off Eley HL, et al. Am J Physiol Endocrinol Metab. 2008;295:E1409-E1416. Adapted from SABiosciences, a QIAGEN company. Available at: http://www.sabiosciences.com/pathway.php?sn=mTOR_Pathway. Accessed June 27, 2011.

  15. Effects of HMB on Phosphorylation Status of mTOR Pathway Signaling Factors • HMB increased phosphorylation of mTOR signaling factors, stimulating protein synthesis • HMB attenuates the depressive effects of proteolysis-inducing factor on protein synthesis p mTOR Total mTOR 0.9 a 0.8 0.7 0.6 0.5 Densitometry units, ph/tot 0.4 0.3 0.2 0.1 0 -2 -1 0 2 Time, h p P70S6K Total P70S6K b 1.6 1.4 1.2 1.0 0.8 Densitometry units, ph/tot 0.6 0.4 0.2 0 -2 -1 0 2 Time, h HMB (50 M) added here to murine myotubes. aDifferent from control, P < .05 bDifferent from control, P < .01 Abbreviations: 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.

  16. β-Hydroxy-β-Methylbutyrate (HMB) HMB and indicators of muscle damage

  17. Evidence for a Protective Effect of HMB Against Muscle Cell Membrane Disruption • Exercise can result in muscle cell membrane disruption1,2 • Elevations of creatine kinase (CK) and other enzyme (eg, lactate dehydrogenase [LDH]) levels in the blood can be indicators of muscle cell membrane disruption3,4 • Not necessarily muscle protein breakdown • A few exercise studies have found a blunted CK response during HMB supplementation5,6 • McBride JM, et al. Med Sci Sports Exerc. 1998;30(1):67-72. • Hurley BF, et al. Int J Sports Med. 1995;16(6):378-384. • 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):325-334. • Knitter AE, et al. J Appl Physiol. 2000;89:1340-1344. • van Someren KA, et al. Int J Sport Nutr Exerc Metab. 2005;15(4):413-424.

  18. Effect 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/wk • Participants received 3 g HMB or placebo daily for 6 weeks before a prolonged run (double-blind) • Pair-matched based on best 2-mile run time • The run was 20 km on a collegiate cross-country course • CK 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 run • Results follow on next slide Knitter AE, et al. J Appl Physiol. 2000;89:1340-1344.

  19. 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 interaction • A significant main effect for treatment in LDH measurement (P = .003), with no significant group × time interaction 450 Placebo HMB 400 350 300 250 CPK activity, U/L 200 150 100 50 0 Pre Post 1d Post 2d Post 3d Post 4d Post Time relative to the prolonged run Reprinted from Knitter AE, et al. J Appl Physiol. 2000;89:1340-1344.

  20. Effects 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)1 • In 6 nonresistance-trained male subjects • Supplementation reduced the delayed onset of muscle soreness (DOMS) ratings (P < .05) • Blunted CK response and decrement of 1-repetition maximum • Several studies did not show any effects of HMB on muscle damage2-5 • However, a major difference between the positive HMB studies and the studies without any effect is the length of supplementation • Ranged from a single acute HMB administration (3 g) before or after exercise to 11 days of supplementation (3 g/day) before exercise • In addition, 1 study showing no effects of HMB/KIC supplementation on muscle damage involved intensive exercise (40 minutes of downhill running)4 • Any supplementation may not reduce that level of muscle damage • Although not significant, a trend was observed toward more rapid recovery of muscle function with HMB/KIC supplementation • van Someren KA, et al. Int J Sport Nutr Exerc Metab. 2005;15(4):413-424. • Wilson JM, et al. Nutr Metab (Lond). 2009;6:6. DOI:10.1186/1743-7075-6-6. • Paddon-Jones D, et al. Int J Sport Nutr Exerc Metab. 2001;11(4):442-450. • Nunan D, et al. J Strength Cond Res. 2010;24(2):531-537. • Hoffman JR, et al. J Strength Cond Res. 2004;18(4):747-752.

  21. β-Hydroxy-β-Methylbutyrate (HMB) Effects of HMB on body composition and strength

  22. Historical Background on HMB Supplementation • Numerous studies of HMB supplementation in several animal models (steers, lambs, rats, chickens, trout, and horses) showed positive effects on • Carcass quality, protein metabolism, immune response, muscle damage, antioxidant status, and blood lipid profile • Dr. Steve Nissen (Animal Science, Iowa State University) is essentially the “father” of the HMB story • Performed initial human studies of HMB supplementation in the 1990s1 • Also performed a meta-analysis of supplementation studies in 2003 with respect to effects on lean body mass and strength gains2 • Nissen S, et al. J Appl Physiol. 1996;81(5):2095-2104. • Nissen SL and Sharp RL. J Appl Physiol. 2003;94:651-659.

  23. Change in Overall Muscle Strength DuringHMB Supplementation: Initial Study • 41 healthy young adults (19-29 years), untrained • 2 protein levels: 117 g/day (control) or 175 g/day • Diet was controlled, nutrient powder in a shake • 3 HMB supplementation doses randomized and blinded within each protein group • 0, 1.5, or 3.0 g/day • Mixed in orange juice • Weight training for 1.5 hours 3 days/week for 3 weeks • Data from control and high protein groups were pooled because there was no difference in HMB results • Overall muscle strength increased at 3 weeks • 8% in control group • 13% in 1.5 g HMB group • 18% in 3.0 g HMB group 800 b Control 1.5 g HMB 3.0 g HMB b 600 c 400 a Change in total body strength, kg 200 0 -200 Week 3 Week 1 aP < .03 bP < .02 cP < .01 Reprinted from Nissen S, et al. J Appl Physiol. 1996;81(5):2095-2104.

  24. Change in Urinary 3-Methylhistidine (3-MH) Excretion DuringHMB Supplementation: Initial Study • 3-MH is a muscle-specific amino acid • Formed during breakdown of muscle proteins (actin and myosin) • Excreted unchanged in urine • HMB supplementation reduced the physiologic increase in 3-MH during exercise • Total muscle breakdown per day increased from 3% at baseline to • 6% at week 3 in control group • 5.5% at week 3 in 1.5 g HMB group • 4.5% at week 3 in 3.0 g HMB group 100 Control 1.5 g HMB 3.0 g HMB 80 a 60 40 % Change in 3-MH from basal b 20 0 -20 aP < .04 bP < .001 Week 1 Week 2 Week 3 Reprinted from Nissen S, et al. J Appl Physiol. 1996;81(5):2095-2104. Elia M, et al. Br Med J. 1981;282:351-354.

  25. Change 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 table • Randomized to placebo or 3 g HMB per day for 7 weeks • HMB provided in a nutrient/protein powder; placebo was isocaloric orange juice • Participants 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/week • Total body electrical conductivity (TOBEC) was used for body composition analysis • HMB supplementation increased fat-free mass early in exercise regimen compared with placebo • Significant gains continued through day 39 a a a 3.50 a 2.50 1.50 Fat-free mass gain, kg 0.50 -0.50 Placebo HMB + nutrient powder -1.50 0 10 20 30 40 50 Day of study aP < .05 Reprinted from Nissen S, et al. J Appl Physiol. 1996;81(5):2095-2104.

  26. Positive Effects of HMB Supplementation on Strength, Power, and/or Body Composition 26

  27. Studies Showing No Effects of HMB Supplementation on Strength and Body Composition

  28. Why the Discrepancy in HMB Studies? • There are potential differences in muscle metabolism between more highly trained and untrained athletes • More potential for benefit probably in untrained athletes • Length of HMB supplementation may have been insufficient in negative studies • More 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/day • Larger body size might require a larger dose • Type of training may be important • Differences between laboratories • There are several good meta-analyses and reviews of HMB and athletic performance1-6 • Portal S, et al. J Ped Endocrinol Metab. 2010;23(7):641-650. • Zanchi NE, et al. Amino Acids. 2011;40(4):1015-1025. • Alon T, et al. Res Comm Mol Pathol Pharmacol. 2002;111(1-4):139-151. • Nissen SL and Sharp RL. J Appl Physiol. 2003;94:651-659. • Rowlands DS and Thomson JS. J Strength Cond Res. 2009;23(3):836-846. • Wilson GJ, et al. Nutr Metab. 2008;5:1 DOI:10.1186/1743-7075-5-1.

  29. Counterfeit HMB? • The initial human research on HMB came from Steve Nissen’s laboratory at Iowa State • The compound they studied and the one in their associated patents calcium -hydroxy--methylbutyrate • A product marketed in the UK (HMB-1000, Maximuscle Ltd.) has been shown in one study to be ineffective at reducing exercise-induced muscle damage1 • Subsequent analysis of the HMB-1000 product revealed that it actually contained no HMB2 • It 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 activity 1Nunan et al. J Strength Cond Res 2010;24:531-537. 2Abumrad NN, Rathmacher JA. J Strength Cond Res 2011:25(7):1-2.

  30. β-Hydroxy-β-Methylbutyrate (HMB) HMB and aerobic performance

  31. HMB and Measures of Aerobic Capacity • Most of the research regarding HMB has focused on strength and body composition • Ability to train harder with less muscle breakdown from exercise may be a mechanism through which HMB could facilitate aerobic performance • 2 studies have evaluated aerobic capacity during HMB supplementation1,2 • In these studies, the mechanism of how HMB might work is not clear • Vukovich MD and Dreifort GD. J Strength Cond Res. 2001;15(4):491-497. • Lamboley CR, et al. Int J Sport Nutr Exerc Metab. 2007;17(1):56-69.

  32. Measures of Aerobic Capacity: Study 1 • Randomized, double-blind, crossover study involving 8 endurance-trained cyclists • Received 3 g/day HMB, leucine, or placebo for three 2-week supplementation periods, with 2-week washout periods in between • Participants performed graded cycle ergometry tests • VO2peak, VO2max , and lactate accumulation peak were similar between all groups • Onset 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 parameters • Lactate threshold (% VO2max) , and time to reach VO2peak were also increased in the HMB group compared with the leucine and placebo groups • Blood HMB levels were much lower (40- to 60-fold) in the leucine group versus the HMB group • Supports previous data on low conversion rates of leucine to HMB Vukovich MD and Dreifort GD. J Strength Cond Res. 2001;15(4):491-497.

  33. Measures of Aerobic Capacity: Study 2 • Randomized study involving 16 college students • Received 3 g/day HMB or placebo for 5 weeks • Students performed interval training 3 times/week on a treadmill • Compared with the placebo group at 5 weeks, the HMB group had • Increased VO2max (13.4% vs 8.4% for placebo; P < .05) • Increased respiratory compensation point • Decreased time to exhaustion at maximal oxygen consumption (Tmax) • This was largely a function of the greater increase in VO2max • The larger the VO2max, the tougher it is to run at that intensity Lamboley CR, et al. Int J Sport Nutr Exerc Metab. 2007;17(1):56-69.

  34. β-Hydroxy-β-Methylbutyrate (HMB) HMB studies with creatine or with amino acids

  35. HMB in Combination With Creatine • A natural question is whether synergistic or additive effects will occur during simultaneous supplementation with creatine and HMB • Clinical data have reported mixed results • Randomized, double-blind study involving 40 volunteers • Received 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 weeks • Volunteers performed progressive resistance training • Lean 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 placebo • Significant 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 HMB • Reduction 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):558-566.

  36. HMB in Combination With Creatine • Randomized study in basketball players1 • Received creatine, HMB, creatine and HMB, or placebo for 30 days • Doses were not specified • Players in the combination group had increased maximum power and total work output compared with the other groups • No additional increase in lactate or fall in muscle pH • 2 studies did not show benefits of the creatine/HMB combination2,3 • Both 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 weeks • No benefits were observed on • Muscular strength and endurance • Leg power • Anthropometry • Aerobic ability • Anaerobic ability • Zajac A, et al. J Hum Kinet. 2003;10:95-108. • O’Connor DM and Crowe MJ. J Strength Cond Res. 2007;21(2):419-423. • O’Connor DM and Crowe MJ. J Sports Med Phys Fitness. 2003;43(1):64-68.

  37. HMB 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 weeks • MA formula = 1.5 g HMB, 7 g glutamine, 7 g arginine, 3 g taurine, 5.8 g dextrose • Control = 10 g glycine, 11.5 g alanine, 1.5 g glutamate, 1.5 g serine • Volunteers 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 week • Outcome variables • Strength (1-RM) • Vertical jump power • Hormonal and muscle damage responses to an acute bout of resistance training • Body composition and circumferences • Tendon size • Results follow on next slides Kraemer WJ, et al. Med Sci Sports Exerc. 2009;41(5):1111-1121.

  38. Body Composition Changes During Supplementation WithHMB and Amino Acids • Body mass and lean body mass continuously increased in both groups • Body fat continuously decreased in both groups • After 12 weeks of training, the supplementation group had significantly improved body composition C B A CON MA CON MA CON MA 80 95 32 a,b 75 a,b 30 90 a 28 70 a a 85 26 a,b 65 Lean body mass, kg Body fat, % Body mass, kg 24 80 22 60 20 75 55 18 16 50 70 V1 V5 V8 V1 V5 V8 V1 V5 V8 Time point Time point Time point aSignificant difference from V1, P .05 bSignificant difference from control, P .05 Abbreviations: V1, before training; V5, after 6 wks; V8, after 12 wks. Kraemer WJ, et al. Med Sci Sports Exerc. 2009;41(5):1111-1121.

  39. Strength and Power Changes During Supplementation WithHMB and Amino Acids • Both muscle strength and power continuously increased in both groups • After 6 weeks of training, the supplementation group had significantly improved muscle strength that remained enhanced at the 12-week assessment • At 12 weeks, the supplementation group had significantly improved muscle power C A B CON MA CON MA CON MA a,b 6000 a,b a,b 120 a 140 a,b 5500 a a,b 5000 100 a a 120 Vertical jump power, w Bench, kg Squat, kg 4500 80 4000 100 3500 60 3000 80 V1 V5 V8 V1 V5 V8 V1 V5 V8 Time point Time point Time point aSignificant difference from V1, P .05 bSignificant difference from control, P .05 Abbreviations: V1, before training; V5, after 6 wks; V8, after 12 wks. Kraemer WJ, et al. Med Sci Sports Exerc. 2009;41(5):1111-1121.

  40. Changes in Hormone Levels and Indicators of Muscle Damage During Supplementation WithHMB and Amino Acids • Compared with the placebo group, the supplementation group had • Increased resting and exercise-induced testosterone levels • Increase resting growth hormone concentrations • Reduced pre-exercise cortisol concentrations • Attenuated circulating creatine kinase and malondialdehyde concentrations • Indicative of less muscle damage • In general, the effects from supplementation on creatine kinase, malondialdehyde, and cortisol were more pronounced at the 12-week point in the study • No dietary intake data were reported for the study Kraemer WJ, et al. Med Sci Sports Exerc. 2009;41(5):1111-1121.

  41. β-Hydroxy-β-Methylbutyrate (HMB) HMB in the elderly and therapeutic/medical applications

  42. HMB in the Elderly • There are a number of nutritional problems in the elderly population for which there may be applications for HMB • Sarcopenia due to aging and inactivity1 • Bedrest • Inability to perform exercise that can help maintain muscle mass • Wound healing (eg, decubiti)2 • Presence of disease states (eg, cancer, congestive heart failure) associated with significant cachexia3,4 • Generalized malnutrition5 • HMB has been studied in both healthy elderly and those with various conditions associated with loss of muscle mass and wound healing capacity • Baier S, et al. JPEN J Parenter Enteral Nutr 2009;33(1):71-82. • Williams JZ, et al. Ann Surg. 2002;236(3):369-375. • Hsieh LC, et al. Asia Pac J Clin Nutr. 2006;15(4):544-550. • May PE, et al. Am J Surg. 2002;183(4):471-479. • Hsieh LC, et al. Asia Pac J Clin Nutr. 2010;19(2):200-208.

  43. Body 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 age1 • Received 3 g/day HMB or placebo for 8 weeks • Participants underwent an exercise program 5 day/week • 2 randomized, double-blind studies involving 127 elderly adults (N = 50, all women; N = 77, men 38 and women 39)2,3 • Received 2 to 3 g HMB + 1.5 to 2.25 g lysine + 5 to 7.5 g arginine per day or isocaloric, isonitrogenous placebo • Study durations were 12 weeks2 and 1 year3 • No exercise component • General findings from these studies • Some improvements in body composition (lean mass,  fat mass) • Increased protein turnover • Improvement in selected measures of strength and functional tests • Improvements did not always occur in either placebo or HMB group • Indicates that the participants might not have been able to do the exercises adequately • Benefits were stronger during the earlier period of the studies and tapered toward the study end • Vukovich MD, et al. J Nutr. 2001;131:2049-2052. • Flakoll P, et al. Nutrition. 2004;20(5):445-451. • Baier S, et al. JPEN J Parenter Enteral Nutr. 2009;33(1):71-82.

  44. HMB and Wound Healing • Effects of HMB on body composition and protein turnover led to investigations of HMB effects on collagen synthesis and wound healing • Randomized 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 deltoid • Received 14 g arginine + 3 g HMB + 14 g glutamine per day (n = 18) or an isocaloric, isonitrogenous control (n = 17) for 2 weeks • At 2 weeks posttreatment • Hydroxyproline 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 groups • Total α-amino nitrogen (surrogate for total wound protein synthesis) was also similar between groups • However, baseline characteristics of the 2 groups were not presented • Comparable baseline wound healing is not established Williams JZ, et al. Ann Surg. 2002;236(3):369-375.

  45. HMB 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 months • Received 3 g HMB + 14 g glutamine + 14 g arginine per day or placebo (maltodextrin, isocaloric) for 8 weeks • Would have been better to also have isonitrogenous placebo • Outcome variables • Body composition by air displacement plethysmography and skinfolds • T-cell subsets • Change in viral load • Results follow on next slide Clark RH, et al. JPEN J Parenter Enteral Nutr. 2000;24(3):133-139.

  46. Outcomes During Supplementation WithHMB and Amino Acids in HIV-Infected Patients • Body composition improved in the supplementation group compared with the placebo group • Differences were significant within 8 weeks • T-cell subsets (CD3 and CD5) were also increased significantly in the supplementation group compared with the placebo group • Viral load decreased significantly with HMB/Arg/Glut supplementation compared with placebo 5 Placebo HMB/Arg/Gln 3 b Placebo HMB/Arg/Gln 4 2 3 a 2 Cumulative weight gain, kg 1 Cumulative lean gain, kg 1 0 0 -1 -1 4 weeks Start 4 weeks Start 8 weeks 8 weeks aP= .009 bP = .003 Reprinted with permission from Clark RH, et al. JPEN J Parenter Enteral Nutr. 2000;24(3):133-139.

  47. Other PositiveHMB Studies in Cachectic-Prone Populations • Studies with 3 g HMB + 14 g glutamine 14 g arginine per day • Randomized, double-blind study involving 32 patients with solid tumors who had unintentional weight loss > 5%1 • Received HMB/arginine/glutamine, or isonitrogenous, isocaloric placebo for 24 weeks • By 4 weeks, gains in body weight and fat-free mass were observed in the supplementation group compared with the placebo group • At 23 weeks, positive effects from the supplementation were maintained • Randomized, blinded study involving 100 critically ill trauma patients2 • Received HMG, HMB/arginine/glutamine, or isonitrogenous, isocaloric placebo for 28 days • After 7 days of supplementation • Nitrogen 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 supplementation • May PE, et al. Am J Surg. 2002;183(4):471-479. • Kuhls DA, et al. J Trauma. 2007;62(1):125-132.

  48. Other PositiveHMB Studies in Cachectic-Prone Populations • Studies with HMB alone1,2 • In 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 group • In 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 group • Hsieh LC, et al. Asia Pac J Clin Nutr. 2006;15(4):544-550. • Hsieh LC, et al. Asia Pac J Clin Nutr. 2010;19(2):200-208.

  49. Studies Showing No Effects of HMB/Arginine/Glutamine Supplementation • Randomized study involving 40 patients with rheumatoid cachexia1 • Received HMB/arginine/glutamine or isocaloric, isonitrogenous placebo for 12 weeks • Similar improvements in body composition and physical function were reported in both groups • Patients receiving supplementation were less cachectic vs other studies • However, the May PE, et al. study had high dropout rate due to very sick population • Randomized study involving 30 patients undergoing laparoscopic gastric bypass surgery2 • Received 24 g HMB/arginine/glutamine twice daily or no supplementation post-operatively for 8 weeks • No differences between groups in changes of body weight, composition, or resting metabolic rate • No adverse effects on weight loss • Marcora S, et al. Clin Nutr. 2005;24(3):442-454. • Clements RH, et al. Surg Endosc. 2010;25(5):1376-1382.

  50. β-Hydroxy-β-Methylbutyrate (HMB) HMB: Safety

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