The Muscle Anabolic Threshold Concept for an Adapted and Efficient Nutrition during Catabolic States

(1)

The Muscle Anabolic Threshold Concept

for an Adapted and Efficient

Nutrition during Catabolic States

Human Nutrition Unit

Metabolism & Health

Dardevet Dominique, Rémond Didier, Peyron Marie-Agnès, Papet Isabelle,

Savary-Auzeloux Isabelle

_{and Mosoni Laurent.}

(2)

Impact of muscle loss in health and diseases

Muscle loss

Muscle Weakness

Higher risk

of falls

Reduction of

physical

Activity

Energy Expenditure

Fat oxidation

Visceral and tissue

Lipid accumulation

Insulin Resistance

AA

Immunity

(3)

Protein metabolism

Protein Synthesis

Proteolysis

Amino acids

Proteins

Bioavailability of dietary

amino acids

Anabolic factors

(Insulin)

(4)

Protein metabolism

Anabolic response

(Gain of muscle proteins)

Post-absorptive

Food intake

Catabolism

(Loss of muscle proteins)

Postprandial

Post prandial protein gain should compensate the post

absorptive loss of proteins

(5)

Fasted

Normal

0

2

4

6

8

10

Fed

*

0

2

4

6

8

10 Protein synthesis

Proteolysis

F S R % /d F BR % /d

Anabolic

resistance

Impaired anabolic response

to food intake (with the RDA)

Muscle loss

In situations of

muscle mass loss

(6)

Time

The Anabolic Threshold Concept

Anabolic factors

(Amino acids)

Anabolic response Intensity Anabolic response Intensity Anabolic threshold to reach

Food

intake

Duration of the anabolic response

(7)

The Anabolic Threshold Concept

Dardevet et al.

Scientific World Journal, 2012

Anabolic response Intensity Anabolic response Intensity Anabolic threshold to reach

Anabolic response Intensity Anabolic response Intensity Increase of the Anabolic threshold to reach

(8)

Protein metabolism in anabolic resistance situations

Anabolic response

(Gain of muscle proteins)

Post-absorptive

Food intake

Catabolism

(Loss of muscle proteins)

Postprandial

Post prandial protein gain does not compensate the

(9)

The Anabolic Threshold Concept

Dardevet et al. Scientific World Journal, 2012

Anabolic response Intensity Anabolic response Intensity Increase of the Anabolic threshold to reach

Anabolic response Intensity Increase of the Anabolic threshold to reach Anabolic response Intensity Increased Anabolic response Intensity

(10)

The Anabolic Threshold Concept

Dardevet et al. World Scientific Journal, 2012

In situations of muscle loss and

anabolic resistance:

Is Leucine capable to overcome the

increase of muscle anabolic threshold?

3 contrasted situations

Cancer cachexia

Sarcopenia (aging)

(11)

Leucine= a signal nutrient

Protein Synthesis

Leucine

Rheb Gbl.mTOR.raptor 4E-BP1 p70S6K (S6K1) eIF4E rp6

+

Cell membrane

(12)

Cancer and muscle loss

Free Leucine supplementation

Improvement of nitrogen balance

Daily et al. 1983

Improvement of body weight

Tayek et al. 1986

4 g of leucine 29 months

Improvement of muscle strength

Poon et al. 2004

8,7g to 14,6g leucine/kg dietary proteins in the diet

Improvement of muscle mass

Peters et al. 2011

1g /kg body weight

Improve muscle protein synthesis

Improvement of muscle mass

(13)

Free Leucine supplementation in a meal

Fasted

(Mosoni et al, 1995)

Adult

0

2

4

6

8

10 Fed

*

Aged

%/j

Muscle Protein Synthesis

Sarcopenia and aging

Anabolic

resistance

(14)

Leucine , Sarcopenia and Aging

Control

Leucine

* * * * * * * * * 0 - 60 0 60 120 180 240 300 Time (min) 100 200 300 400

Pl

as

ma

Le

uc

ine

Meal 0 0.02 0.04 0.06 0.08 0.10

Pr

o

te

in

s

yn

th

e

si

s

Control

Leucine

*

+57%

Rieu et al, 2006

Katsanos et al. 2006

(15)

Negative on muscle mass and

strength

(Verhoven et al. 2009):

3 months

7.5 g leucine / day

6 -10 months

4.5% leucine in the

diet

Negative on muscle mass

(Zeanandin et al. 2012)

Vianna et al. 2011

(16)

Leucine, Muscle loss and Bed rest/Immobilization

0 0,01 0,02 0,03 0,04 0,05 0,06 0,07 0,08

Post-prandial Stimulation of

Muscle Protein Synthesis (% /h)

(Glover at al. 2008)

*

Free Leucine supplementation

3.1g leucine , 28 days:

Improvement of post prandial muscle

protein synthesis

No change in muscle mas loss

Paddon-Jones et al. 2004

3.6g leucine , 60 days:

No change in muscle mas loss

Trappe et al. 2007

3.6g leucine , 60 days:

No change in muscle strength

Trappe et al. 2008

4,5% leucine in the diet

No change in muscle mass recovery

(17)

20 amino

acids

Muscle protein

synthesis

Digestion time

+ Leucine

Increased Anabolic Threshold

Time

Leucine

Other

Amino acids

(18)

Dardevet et al. Scientific World Journal, 2012 Anabolic response Intensity Anabolic response Intensity Increase of the Anabolic threshold to reach

Anabolic response Intensity Increased Anabolic response Intensity

Why free leucine supplementation disappointing?

Leucine signal

Amino acid availability

Leucine

(19)

Leucine signal

Resynchronisation leucine signal/amino acids

Synchronization

possible with leucine

rich proteins rapidly

digested

(20)

Leucine supplementation with whey

Muscle Recovery Post-immobilization

Post prandial

Protein Synthesis

80 100 120 140 160 180 200

*

Muscle mass

gain (mg)

-300 -200 -100 0 100 200 300 400 500 600 700

20

40

Days of recovery

Magne et al. 2012

Control

+ Leucine

*

Whey

*

(21)

Leucine supplementation with whey

Sarcopenia and Aging

50 100 150 200

Controls

Whey

*

Dangin et al., 2002, 2003; Boirie et al, 1997

Protein Synthesis

Rieu et al, 2007 Mosoni et al. 2013 2,0 2,5 3,0 3,5 4,0 4,5 5,0 5,5 6,0 0,00 0,50 1,00 1,50 2,00 2,50 3,00

Controls

Whey

Protein Synthesis

Muscle mass (10 d or 6 months)

(22)

Leucine signal

When Resynchronisation remained inefficient?

Decrease of the anabolic threshold

Increase more the protein intake

Interaction between protein and

(23)

Leucine signal

When Resynchronisation is inefficient?

Decrease the

anabolic threshold

Anabolic

response Intensity Increased Anabolic response Intensity

Leucine signal

(24)

Leucine signal

When Resynchronisation is inefficient?

Leucine signal

(25)

How to decrease the anabolic threshold?

Most of the stituations of muscle loss are

associated with an increase of :

Inflammation and Oxidative Stress

Muscle

Anabolism

Cytokines TNF

a

, IL

1

, IL

6

O

₂

°

Oxidative

Stress

Inflammation

(26)

How to decrease the anabolic threshold?

Rutin, vitamin E, vitamin A,

Zn et Se for 7 weeks

1.2

1.4

1.6

1.8

2.0 Leucine concentration

1.2

1.4

1.6

1.8

2.0

0 100 200 300 400 µM

*

Aged

Aged + Antioxidants

*

3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8

Ibuprofen

CT

M

usc

le

M

a

s

(

g)

_+10.6%

*

Marzani et al. J Nutr 2008 Mosoni et al. Nutrition, 2010

P

rot

ei

n

sy

nthes

is

(

%

/d)

+ Ibuprofen

*

2.5 3.0 3.5 4.0 4.5 5.0 5.5 Postabsorptive Postprandial

No Inf

Low Grade Inf

P

rot

e

in

s

y

nt

he

s

is

(

%

/d)

Rieu I, J Physiol 2009 Balage et al. JNB, 2010

(27)

Leucine signal

When Resynchronisation is inefficient?

Increase more

the protein intake?

(28)

Increase of dietary protein

intake

High protein diet: The protein pulse feeding?

Post prandial time

Anabolic factors

(Amino acids)

Food

intake

(29)

Anabolic response Intensity Anabolic response Intensity

The protein pulse feeding?

Time Anabolic factors (Amino acids) Food intake Postabsorptive concentrations

Increase of the dietary protein intake

(30)

Increase of the dietary protein intake

Breakfast Diner

Lunch

Pulse protein diet

Lunch Breakfast

Tea time

Spread protein diet

Diner Pulse Spread 0 10 20 30 40 50 60 70 80

Agé

Adulte

(Arnal et al. 1999,2002 Bouillanne et al. 2013)

(31)

Leucine signal

When Resynchronisation is inefficient?

Interaction with protein

and energy intake?

(32)

Amino acids

mTOR

> 180 min

Muscle protein synthesis

< 180 min

0,0

1,0

2,0

3,0

4,0

5,0

-25 0 25 50 75 100 150 200 250 300

< 180 min

Existence of « Stop Signals »

stronger than the anabolic

signals !!

When Resynchronisation is inefficient? Whey too fast?

(33)

What is the “Stop signal”?

Muscle protein synthesis

< 180 min

0,0

1,0

2,0

3,0

4,0

5,0

-25 0 25 50 75 100 150 200 250 300

< 180 min

0

50

100

150

200

-25 0 25 50 75 100 150 200 250 300

AMPK activity

AMPK

Activity increases when ATP

decreases

Protein synthesis has a high

energetic cost

(34)

Nutritional strategy to take into account AMPK?

Prevent the AMPK activity to increase

Maintain the muscle ATP levels as long as possible during the

post prandial period

muscle ATP levels

0

50

100

150

200

250

-25 0 25 50 75 100 125 150 175 200 225 250 275 300

Energy intake

between 90 and

180 min after the

beginning of the

(35)

0

50

100

150

200

-25 0 25 50 75 100 150 200 250 300

0

50

100

150

200

250

300

-25 0 25 50 75 100 150 200 250 300

0

1

2

3

4

5

-25 0 25 50 75 100 150 200 250 300

AMPK

Muscle ATP

Muscle protein synthesis

Energetic chrononutrition?

Meal with whey proteins

Meal with whey proteins and

energetic bolus 90 min later

(36)

Conclusions

If leucine given as a free amino acid over a normal protein diet

May be inefficient in several situations

Desynchronization with the other amino acids

Synchronization of leucine with the other amino acids is possible

with leucine rich proteins

Whey

Leucine is indeed a

very good stimulator

muscle protein synthesis

A nutritional strategy efficient in one situation of muscle wasting

may not be efficient in an another one

Intensity of the anabolic resistance

Duration of this anabolic resistance

(37)

Dietary Whey supplementation: Matrix effect?

Process of the

milk protein sources

Milk

Barbé et al., 2013

Time (min) 0 500 1000 1500 2000 2500 3000 3500 0 30 60 90 120 150 180 210 240 270

Milk

Gelation

Acidic gelation

Rennet gelation

Decreased digestion speed

Decreased of amino acid bioavailability

(38)

Matrix effect: Which consequences ?

Time (min)

0

500 1000

1500

2000

2500

3000

3500

0 30 60 90 120 150 180 210 240 270

Milk

Acidic gelation

Rennet gelation

Anabolic threshold

In normal healthy situations

Processes has limited impact

In anabolic resistance situations

Processes blunt the

anabolic effect of milk

(39)

Conclusions

Prolonged and better efficiency of whey proteins if the anabolic

threshold is also controlled

Combination whey and anti-inflammatory and antioxidants

Unknown is the effet of dietary chronic leucine bioavailability

Pro diabetic? Insulin resistance?

So far, only the pulse protein feeding is efficient during aging

Feasibility? In other muscle loss situations?

Long term effect ?

An energetic chrononutrition has to be tested in combination with

whey proteins in (a) real muscle wasting situation(s)

Could the « Stop signal » be a target?

(40)

UNH 1019

Unité de Nutrition Humaine

Métabolismes & Santé

(41)

(42)

Measurement of post prandial

protein synthesis in steady state

Time

Anabolic factors

(Amino acids)

Food

intake

Time

Little Food boluses