β -hydroxy- β -methylbutyrate (hmb)
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DESCRIPTIONβ -Hydroxy- β -Methylbutyrate (HMB). Educational Objectives for the β -Hydroxy- β -Methylbutyrate (HMB) Presentation. Provide a general overview of HMB intake and metabolism - PowerPoint PPT Presentation
-Hydroxy--Methylbutyrate (HMB)11Educational Objectives for the -Hydroxy--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 supplementation22-Hydroxy--Methylbutyrate (HMB)3General overview of intake and metabolism3What Is HMB?HMB is a leucine metaboliteLeucine 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 -ketoisocaproate (KIC) by branched-chain amino acid transferase, mainly in muscle tissuesApproximately 5% to 10% of -ketoisocaproate (KIC) is converted to HMB (by KIC-dioxygenase) in the cell cytosolCalcium HMB has the following molecular structural formula2Nemet D, et al. IMAJ. 2005;7:328-332.Available at: www.chemblink.com/products/135236-72-5.htm. Accessed May 10, 2011. Ca++HOOOOOOH44Formation of HMB During Leucine MetabolismAdapted with permission from Nissen SL and Abumrad NN. J Nutr Biochem. 1997;8(6):300-311.LeucineKICIsovaleryl-CoA-methyl-crotonyl-CoA(MC-CoA)-hydroxy--methylbutyrate(HMB)HMB-CoAHMG-CoAMevalonateAcetyl-CoACholesterol(5-10% of Leu metabolism)Acetoacetyl-CoA(only whenbiotin is deficient)55Sources of HMB in the DietCatabolism of leucineMean intake of leucine from food and supplements (1988-1994 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, 30-60 g leucine/day would have to be consumedHMB in foodsThere 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, 2011.66HMB Absorption and KineticsThe 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):631-639.77HMB BioavailabilityReprinted from Fuller JC Jr, et al. Br J Nutr. 2011;105:367-372.Bioavailability 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 salta P < .05bP < .01cP < .0001ccbaaa3002502001501005000200400600800100012001400Time, minHMB, mol/l plasmaCalcium HMB capsulesFree acid HMB gel conditionsccc88-Hydroxy--Methylbutyrate (HMB)9Mechanisms of action9Possible HMB Mechanisms of ActionHMB may be an anticatabolic agentStudies 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 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)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. J Nutr 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):1015-1025.1010The Ubiquitin-Proteasome Pathway for Protein DegradationReprinted from Lecker SH, et al. J Nutr. 1999;129:227S-237S.
1111Effects of HMB on the Ubiquitin-Proteasome PathwayReprinted from Smith HJ, et al. Cancer Res. 2005;65:277-283.a P < .005Study performed in tumor-bearing (MAC16) mice that were treated for 3 days withOlive oil/phosphate-buffered saline (control)-hydroxy--methylbutyrate (HMB)Eicosapentaenoic acid (EPA)HMB and EPAChymotrypsin-like enzyme activity (indicator of ubiquitin proteasome pathway) in the gastrocnemius muscle was assessed 2018161412100ControlFluorescent units/h/gram0.25 g/kg HMB0.6 g/kg EPAHMB + EPAaaa86421212Effects of HMB on Protein Synthesis and DegradationInitiator (PIF, LPS, TNF-, angiotensin II, etc.)Caspase-8Caspase-3PKRp38 MAPKPKR PeIF2eIF2 PTranslational efficiencyProtein synthesis ROS NF- (nuclear accumulation)Proteasome + E3 mRNAProtein degradationHMB blocks pathwayhereXPIF, 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-E1426.1313
Further Effects of HMB on Cellular Protein SynthesisHMB increases mTOR signaling pathway activity
mTOR 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: http://www.sabiosciences.com/pathway.php?sn=mTOR_Pathway. Accessed June 27, 2011.1414
0.90.80.70.60.50.40-2Densitometry units, ph/tota0.30.20.1-102Time, hp mTORTotal mTOR
22.214.171.124.00.80-2Densitometry units, ph/totb0.60.40.2-102Time, hp P70S6KTotal P70S6KEffects of HMB on Phosphorylation Status of mTOR Pathway Signaling FactorsReprinted from Eley HL, et al. Am J Physiol Endocrinol Metab. 2007;293:E923-E931.HMB (50 M) added here to murine myotubes.HMB increased phosphorylation of mTOR signaling factors, stimulating protein synthesisHMB attenuates the depressive effects of proteolysis-inducing factor on protein synthesisaDifferent from control, P < .05bDifferent from control, P < .01Abbreviations: mTOR, mammalian target of rapamycin; p, phosphorylation; P70S6k, 70-kDa ribosomal S6 kinase.1515-Hydroxy--Methylbutyrate (HMB)16HMB and indicators of muscle damage16Evidence 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):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):413-424.1717Effect of HMB Supplementation on Creatine Kinase Levels During ExerciseKnitter AE, et al. J Appl Physiol. 2000;89:1340-1344.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 slide1818Effect of HMB Supplementation on Creatine Kinase Levels During Exercise (Contd)Reprinted from Knitter AE, et al. J Appl Physiol. 2000;89:1340-1344.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 interaction4504003503002500PreCPK activity, U/L2001501001dPost3dPostPost2dPost4dPostTime relative to the prolonged run50PlaceboHMB1919Effects of HMB Supplementation on Muscle Damage During Exercise1 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