3/29/2002

Nutritional Strategy

Protein break- down

Metabolic Regulators

Protein synthesis

Energy and amino acids

3/29/2002

CH2-CH2-C-O- Ca+

CH3

OH H3C

O

2

HMB- (����-hydroxy ����-methyl butyrate)

����

3/29/2002

HMB:

Theory: Cholesterol synthesis may limit cell growth/repair at certain times

HMB β-hydroxy-β-methylbutyrate

Leucine KIC CO2

Cholesterol

HMG-CoA

Cell membrane

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Human Studies w/ HMB

Adjunct for muscle building (Comparisons) Safety Combinations Other effects

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HMB and Resistance training

0 0.05 0.1

0.15 0.2

0.25 0.3

0.35 0.4

Ne t g

ai n

le an

(% /w

k)

Nissen et al. 1996

Nissen et al. 1996

Panton 2000

Panton et al. 2000

Kreider et al. 1999

Jowko et al. 2001

Gallagher et al 2000

Slater et al. 2001

Vukovich et al 2001

3/29/2002

No adverse changes *Less negative moodEmotional

No adverse changesBlood hematology

No adverse changes *Lower cholesterol

Blood chemistry

No Adverse effects *Decreased BP Physical

Safety: 3-12 weeks

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Meta-Analysis:

Body composition Minimum 3-weeks Minimum trained 2x per week Placebo controlled Statistical information for ES Protein-(placebo issues)

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Meta-analysis: 250+ included

274Protein

242DHEA

323Androstenedione

3312Chromium

359HMB

3715Creatine

Quality score

Qualified studies

3/29/2002

Lean Tissue Gain

0

0.1

0.2

0.3

0.4

0.5

0.6

% g

ai n

pe r

w ee

k

Creatine HMB Chromium

Androstene...

DHEA Protein

Placebo Treatment *** ***

3/29/2002

Meta-Analysis

-0.10

0.00

0.10

0.20

0.30

Ef fe

ct S

iz e

Creatine HMB

Chromium

Androstenedione

DHEA Protein

0.00

0.05

0.10

0.15

0.20

0.25

Ef fe

ct S

iz e Lean Tissue

Gain

Strength Gain

Significant Effect size

3/29/2002

HMB and Creatine

+++Fat loss (weight training)

++- (risk of muscle

damage)

++ (protect muscle)

Runner benefit

+-++++ (BP and cholesterol

lowered)

Health benefits

+++++++Lean gain (weight training)

CreatineHMB

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Minimizing Muscle damage

0

50

100

150

200

250

C PK

c ha

ng e

(% )

Pre Post Day 1 Day 2 Day 3 Day 4

Placebo

HMB

CPK after a 10K race

3/29/2002

Muscle stress results in tears in cell membrane

Muscle CPK leaks into the blood

CPK is 30-80% lower Less muscle breakdown � Lower 3-

methylhistidine � Lower proteases

Less soreness

HMB effects on Damage

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Other observations

Less Protein turnover (muscle) Young and old: Men and women Effect proportional to intensity Immune function improved

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Non exercising

Sedentary young people � HMB: No demonstrable effect � Creatine: No demonstrable effect

Wasting?

3/29/2002

WastingWastingNormalNormal Protein break- down

Protein synthesisProtein

synthesis

Protein break- down

Mechanism of wasting

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Age-related muscle mass

Age

M us

cl e

m as

s

100% of max

80% of max

70% of max

25 y 50 y

75 y

3/29/2002

Disease-related wasting

Most AIDS patients waste Nearly all stage 2-4 lung, pancreas, colon and upper GI cancers >10% muscle loss=risk

Question: Can targeted nutrition reverse wasting?

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Targeted Nutritional Strategy

Protein break- down

Slow

HMB

Protein synthesis

Enhance

Glutamine

Arginine

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Elderly protocol

Age ~78 years Two replicate experiments Mostly women 12 week study Endpoints: lean tissue/mobility Assisted living 2 g HMB/5 g Arg/ 1.5 g Lysine Once per day

3/29/2002

Body Composition changes

Body lean: +1 kg

-1.5 -1

-0.5 0

0.5 1

1.5 2

2.5 3

% C

ha ng

e ov

er 1

2 w

ks

Iowa TN

Lean change

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Function (Get-Up & Go)

4 6 8 10 12

Get-Up & Go time (sec)

*** +12 wks

Start

Start

+12 wks

PlaceboPlacebo

HMB/ HMB/ Arg /LysArg /Lys

3/29/2002

AIDS/Cancer Protocols

AIDS � Lost >5% BW � 36 subjects/8 wks

Cancer � Lost 10% BW � 40 subjects/8+wks

Mixture � 3 g HMB � 15 g Arginine � 15 g Glutamine

3/29/2002

AIDS/Cancer comparison

-0.7 -1.1

2.5

1.4

-2.5

-1.5

-0.5

0.5

1.5

2.5

3.5 Le

an g

ai n

or lo

ss (

Kg )

AIDS subjects

Cancer subjects

**

**

Placebo

HMB/Arg /Gln

3/29/2002

HMB + amino acid

Targeted nutritional strategy valid Very slight wasting can be reversed Very sever wasting can be reversed Multi-center studies underway

3/29/2002

Muscle-Immune connection

-3

-2

-1

0

1

2

3

Placebo

HMB/Arg/Gln

Placebo vs HMB/Arg/Gln significantly different p

3/29/2002

Summary

250+ nutrition supplements marketed: � Only creatine and HMB meet scientific

threshold for resistance exercise ~Double effect Short-term safety New applications: � Rational Combinations � Targeted