Methylbutyrate (HMB)

Report
β-Hydroxy-β-Methylbutyrate (HMB)
1
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
2
β-Hydroxy-β-Methylbutyrate (HMB)
General overview of intake and metabolism
3
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
–O
Ca++
O–
HO
OH
O
O
1.
2.
Nemet D, et al. IMAJ. 2005;7:328-332.
Available at: www.chemblink.com/products/135236-72-5.htm. Accessed May 10, 2011.
4
Formation of HMB During Leucine Metabolism
Leucine
Isovaleryl-CoA
KIC
(5-10% of
Leu metabolism)
β-hydroxy-β-methylbutyrate
(HMB)
(only when
biotin is deficient)
β-methyl-crotonyl-CoA
(MC-CoA)
HMB-CoA
HMG-CoA
Mevalonate
Acetoacetyl-CoA
Cholesterol
Acetyl-CoA
Adapted with permission from Nissen SL and Abumrad NN. J Nutr Biochem. 1997;8(6):300-311.
5
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
1.
2.
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.
6
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.
7
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
HMB, μmol/l plasma
250
200
c
c
c
Free acid HMB gel conditions
c
150
c
100
b
a
Calcium HMB capsules
50
a
a
a
0
P < .05
0
200
400
bP < .01
cP < .0001
Reprinted from Fuller JC Jr, et al. Br J Nutr. 2011;105:367-372.
600
800
Time, min
1000
1200
1400
8
β-Hydroxy-β-Methylbutyrate (HMB)
Mechanisms of action
9
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
1.
2.
3.
4.
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.
10
The Ubiquitin-Proteasome Pathway for Protein
Degradation
Reprinted from Lecker SH, et al. J Nutr. 1999;129:227S-237S.
11
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
Fluorescent units/h/gram
 Chymotrypsin-like enzyme activity (indicator of ubiquitin proteasome
pathway) in the gastrocnemius muscle was assessed
20
18
16
14
12
10
8
6
4
2
0
Control
a
a
a
a
0.25 g/kg HMB
0.6 g/kg EPA
HMB + EPA
P < .005
Reprinted from Smith HJ, et al. Cancer Res. 2005;65:277-283.
12
Effects of HMB on Protein Synthesis and Degradation
Initiator (PIF, LPS, TNF-, angiotensin II, etc.)
X
HMB blocks pathway
Caspase-8
here
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.
13
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.
14
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
Densitometry units, ph/tot
Total mTOR
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
a
-2
-1
0
2
Time, h
p P70S6K
Densitometry units, ph/tot
Total P70S6K
aDifferent
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0
b
-2
-1
0
2
Time, h
HMB (50 M) added here to murine myotubes.
from control, P < .05
from control, P < .01
Abbreviations: mTOR, mammalian target of rapamycin; p, phosphorylation; P70 S6k, 70-kDa ribosomal S6 kinase.
Reprinted from Eley HL, et al. Am J Physiol Endocrinol Metab. 2007;293:E923-E931.
bDifferent
15
β-Hydroxy-β-Methylbutyrate (HMB)
HMB and indicators of muscle damage
16
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
1.
2.
3.
4.
5.
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.
17
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.
18
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
CPK activity, U/L
450
400
Placebo
350
HMB
300
250
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.
19
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
1.
2.
3.
4.
5.
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.
20
β-Hydroxy-β-Methylbutyrate (HMB)
Effects of HMB on body composition and strength
21
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
1.
2.
Nissen S, et al. J Appl Physiol. 1996;81(5):2095-2104.
Nissen SL and Sharp RL. J Appl Physiol. 2003;94:651-659.
22
Change in Overall Muscle Strength During HMB
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
 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
Change in total body strength, kg
 Weight training for 1.5 hours 3 days/week for 3 weeks
800
600
b
Control
1.5 g HMB
3.0 g HMB
b
c
400
a
200
0
-200
aP
< .03
bP < .02
cP < .01
Reprinted from Nissen S, et al. J Appl Physiol. 1996;81(5):2095-2104.
Week 1
Week 3
23
Change in Urinary 3-Methylhistidine (3-MH) Excretion
During HMB Supplementation: Initial Study
aP
bP
< .04
< .001
% Change in 3-MH from basal
 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
80
Control
1.5 g HMB
3.0 g HMB
a
60
40
b
20
0
-20
Week 1
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.
Week 2
Week 3
24
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
a
Fat-free mass gain, kg
 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
3.50
a
a
2.50
1.50
0.50
-0.50
Placebo
HMB + nutrient powder
-1.50
0
aP
a
10
20
30
Day of study
40
50
< .05
Reprinted from Nissen S, et al. J Appl Physiol. 1996;81(5):2095-2104.
25
Positive Effects of HMB Supplementation on Strength,
Power, and/or Body Composition
Study Design
Treatment
Training
Results
Double-blind in
untrained college
men,
N = 371
0, 38, or 76
mg/kg/day HMB
(equivalent to 0, 3, or
6 g/day) for 8 wks
Resistance,
3 times/wk (80% 1RM) assessed every
2 wks
 Compared 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 groups
Randomized in
trained or untrained
adults (men, 39;
women, 36; age, 2040 year), N = 752
3 g/day HMB or
placebo for 4 wks
Strength,
3 times/wk
(90% 1-RM)
 Compared with placebo group, the HMB group had
Randomized, doubleblind in resistancetrained men (young
adults), N = 223
3 g/day HMB or
placebo for 9 wks
Strength,
3 times/wk
(1-RM)
 Compared with placebo group, the HMB group had
Randomized, doubleblind in elite,
national-team level,
adolescent volleyball
players (men, 14;
women, 14), N = 284
3 g/day HMB or
placebo for first 7
wks of the training
season
Volleyball skills
(20%), power and
speed drills (25%),
interval (25%),
endurance (15%)
and resistance
(circuit-style; 15%),
18-22 hr/wk
 Compared with placebo group, the HMB group had
− Greater increase in upper body strength (P = .008)
− Blunted postexercise rise in creatine kinase vs placebo
− Somewhat greater increase in fat-free mass (P = 0.08)
− 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 composition
− Increased 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 force
 No effects of HMB on aerobic capacity or anabolic
and catabolic hormones
Abbreviations: RM, repetition maximum. 1. Gallagher PM, et al. Med Sci Sports Exerc. 2000;32(12):2109-2115. 2. Panton LB, et al. Nutrition. 2000;16(9):734-739.
3.Thomson JS, et al. J Strength Cond Res. 2009;23(3):827-835. 4. Portal S, et al. Eur J Appl Physiol. 2011;Feb 16:E-pub.
26
Studies Showing No Effects of HMB Supplementation on
Strength and Body Composition
Study Design
Treatment
Training
Results
Randomized, doubleblind in experienced
(5.5 years),
resistance-trained
athletes, N = 401
0, 3, or 6 g/day HMB
for 28 days in a
carbohydrate/protein
powder
Maintained
individualized
resistance training
program (~7 hrs/wk)
and kept training
logs
 Neither dose of HMB influenced
Randomized, doubleblind in national-level
athletes (polo, 17;
rowers, 10) with ≥ 2
years of resistance
training, N = 272
3 g/day HMB (timedrelease or standard
capsule) or placebo
for 6 wks
Resistance,
2-3 times/wk
(Pre-competition
phase of training)
 Neither dose of HMB influenced
Randomized,
crossover in
collegiate football
players, N = 353
3 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 types
 No changes in body composition or strength for
either placebo or HMB groups
Randomized, singleblind in collegiate
football players,
N = 264
3 g/day HMB or
placebo for 10 days
Preseason training
camp
 No changes between baseline and post training in
either placebo or HMB groups for anaerobic power
 No changes between placebo and HMB groups for
changes in creatine kinase, myoglobin,
testosterone, or cortisol levels
− Strength (1-RM)
− Body composition (by dual energy X-ray absorptiometer)
− Body anabolic/catabolic status
− Blood chemistries
− Strength
− Body composition
− Creatine kinase levels
 Trend toward higher creatine kinase level in placebo group
(P = .07 for group x time interaction)
− Lack of change in placebo group suggests overtraining
Abbreviations: RM, repetition maximum. 1. Kreider RB, et al. Int J Sports Med. 1999;20(8):503-509. 2. Slater G, et al. Int J Sport Nutr Exerc Metab. 2001;11(3):384-396.
3. Ransone J, et al. J Strength Cond Res. 2003;17(1):34-39. 4. Hoffman JR, et al. J Strength Cond Res. 2004;18(4):747-752.
27
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
1.
2.
3.
4.
5.
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.
28
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 exerciseinduced 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.
NN, Rathmacher JA. J Strength Cond Res 2011:25(7):1-2.
2Abumrad
β-Hydroxy-β-Methylbutyrate (HMB)
HMB and aerobic performance
30
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
1.
2.
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.
31
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.
32
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.
33
β-Hydroxy-β-Methylbutyrate (HMB)
HMB studies with creatine or with amino acids
34
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.
35
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
1.
2.
3.
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.
36
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.
37
Body Composition Changes During Supplementation
With HMB 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
80
CON
MA
a
85
80
75
MA
75
a,b
Lean body mass, kg
90
CON
CON
32
a,b
MA
30
70
a
65
60
28
Body fat, %
95
Body mass, kg
C
B
A
a
26
a,b
24
22
20
55
18
16
50
70
V1
V5
Time point
V8
V1
V5
Time point
V8
V1
V5
V8
Time point
difference from V1, P  .05
difference from control, P  .05
Abbreviations: V1, before training; V5, after 6 wks; V8, after 12 wks.
aSignificant
bSignificant
Kraemer WJ, et al. Med Sci Sports Exerc. 2009;41(5):1111-1121.
38
Strength and Power Changes During Supplementation
With HMB 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
B
CON
MA
140
CON
a,b
120
a
MA a,b
Bench, kg
Squat, kg
a,b
120
a
100
80
100
CON
6000
a,b
Vertical jump power, w
A
MA
a,b
5500
5000
a
a
4500
4000
3500
60
3000
80
V1
V5
Time point
V8
V1
V5
Time point
V8
V1
V5
V8
Time point
difference from V1, P  .05
difference from control, P  .05
Abbreviations: V1, before training; V5, after 6 wks; V8, after 12 wks.
aSignificant
bSignificant
Kraemer WJ, et al. Med Sci Sports Exerc. 2009;41(5):1111-1121.
39
Changes in Hormone Levels and Indicators of Muscle Damage
During Supplementation With HMB 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.
40
β-Hydroxy-β-Methylbutyrate (HMB)
HMB in the elderly
and therapeutic/medical applications
41
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
1.
2.
3.
4.
5.
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.
42
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
1.
2.
3.
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.
43
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.
44
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.
45
Outcomes During Supplementation With HMB 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
4
Placebo
HMB/Arg/Gln
3
3
a
2
1
0
-1
Start
Cumulative lean gain, kg
Cumulative weight gain, kg
5
b
Placebo
HMB/Arg/Gln
2
1
0
-1
4 weeks
8 weeks
Start
4 weeks
8 weeks
aP =
bP
.009
= .003
Reprinted with permission from Clark RH, et al. JPEN J Parenter Enteral Nutr. 2000;24(3):133-139.
46
Other Positive HMB 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
1.
2.
May PE, et al. Am J Surg. 2002;183(4):471-479.
Kuhls DA, et al. J Trauma. 2007;62(1):125-132.
47
Other Positive HMB 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
1.
2.
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.
48
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
1.
2.
Marcora S, et al. Clin Nutr. 2005;24(3):442-454.
Clements RH, et al. Surg Endosc. 2010;25(5):1376-1382.
49
β-Hydroxy-β-Methylbutyrate (HMB)
HMB: Safety
50
Safety 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 effects
– Decreased mortality (probably due to enhanced immunity)2,3
– Decreased muscle protein breakdown4
– Improved carcass quality (more lean, less fat)5
 A 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 effects6
– This included changes in food consumption and body weight, as well as
clinical chemistries, organ weights, hematology, and macro- and
microscopic tissue examinations
1.
2.
3.
4.
5.
6.
Papet I, et al. Br J Nutr. 1997;77(6):885-896.
Nissen S, et al. Poult Sci. 1994;73(1):137-155.
Peterson AL, et al. Immunopharm Immunotox. 1999;21(2):307-330.
Holecek M, et al. Food Chem Toxicol. 2009;47(1):255-259.
Van Koevering MT, et al. J Anim Sci. 1994;72(8):1927-1935.
Baxter JH, et al. Food Chem Toxicol. 2005;43(12):1731-1741.
51
Safety Profile of HMB: Human Studies
 HMB has been marketed extensively as a dietary supplement since
1996 with no pattern of adverse event reports
 Clinical studies evaluating HMB or HMB + creatine supplementation
for periods of 3 to 8 weeks with doses up to 6 g/day HMB have
shown1-3
– No adverse hematological, hepatic, or renal effects
– Some tendency to decrease total and low-density lipoprotein
cholesterol (–5.8 and –7.3%, respectively) and reduce systolic blood
pressure (–4.4 mm Hg)2
• Although HMB can be used for cholesterol synthesis, it appears that the
cholesterol synthesis is localized (eg, muscle) and does not adversely affect
blood cholesterol levels
 Clinical studies evaluating the combination of
HMB/Arginine/Glutamine in healthy volunteers and patients with
HIV or cancer showed4
– Combination was safe
– Improvement in certain hematological parameters
1.
2.
3.
4.
Gallagher PM, et al. Med Sci Sports Exerc. 2000;32(12):2116-2119.
Nissen S, et al. J Nutr. 2000;130(8):1937-1945.
Crowe MJ, et al. Int J Sport Nutr Exerc Metab. 2003;13(2):184-197.
Rathmacher JA, et al. JPEN J Parenter Enteral Nutr. 2004;28(2):65-75.
52
Additional Information Regarding the Safety of HMB
 No published study has reported any adverse effects of HMB
– However, some of these studies did not report adverse event data as
part of the data presented
 There are very limited data in humans on HMB doses up to
6 g/day
– No treatment-related adverse events were reported
 Most HMB studies in humans have been ≤ 8 weeks
– There are some data out to 24 weeks showing safety
 Data on elderly are limited, but studies reviewed in this
presentation in both healthy and clinical populations have
not reported adverse events
53
HMB Summary
 Primary source of natural HMB is catabolism of the amino acid leucine
 HMB stimulates muscle protein synthesis and may also
– Increase cell membrane integrity via cholesterol synthesis
– Decrease indicators of muscle damage (creatine kinase levels)
– Be an anticatabolic agent
 Clinical results evaluating the benefits of HMB supplementation alone or
with other supplementation on body composition and strength have been
mixed
– Benefits may be reported once an optimal HMB dose and duration that
correlates with an athletes size and training level is established
 Clinical results suggest that HMB improves
– Aerobic performance
– Conditions associated with loss of muscle mass
– Wound healing capacity
 HMB has been reported to be safe and well tolerated
– Data is limited and from short-duration studies
54

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