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Résistance anabolique en situation d’agression

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DIU de Médecine Intensive

Clermont-Fd, 31 Janvier 2013

Pr. Yves BoirieService de Nutrition CliniqueUnité de Nutrition HumaineClermont-Ferrand

Objectifs

• Comprendre la physiopathologie de la résistance anabolique

• Connaître les stratégies thérapeutiques potentielles : – nutritionnelles– physiques– hormonales– médicamenteuses

(1900-1989)

Biochem J, 1937

CHO CHOFat Fat

N excretion

(1900-1989)

EXPLORATIONS DU MÉTABOLISME PROTÉIQUE

Energy impact on nitrogen retention

IncreasingN intake

Nitrogenbalance

0

Protein gain

Nitrogenrequirement

Energy deficit

Nitrogenrequirement

Circadian rythm of nitrogen balance

IncreasingN intake

NitrogenBalance

(in – out)

0

FED STATE (12h)

Price, Clin Sci 1994

Protein gain

POSTABSORPTIVE (12h)

Protein loss

Tracer:labeled AA

Samples

isot

opic

en

richm

ent

t

- Tracers- Models- Analysis- Calculations

Protein kinetics using stable isotopes

freeAA

(70 g)

Proteins(10 kg)

Synthesis (300 g/d)

Proteolysis (300 g/d)

Schematic overview of whole body protein metabolism in humans

Intake (70 g/d)

Oxidation (70 g/d)

de novo AA synthesis

AA conversiontransformation

FreeAA

ProteinsSynthesis

intake = 0

OxidationProteolytic systems - Calpaïns- Lysosomal- Ub-proteasome

Schematic representation of protein metabolism

Proteolysis

FreeAA

ProteinsSynthesis

intake

Oxidation

Schematic representation of protein metabolism

Proteolysis

controlstrauma

Mansoor O, PNAS 1996

-1

-0,5

0

0,5

1

1,5

2

2,5

3

breakdownleuc

ine

flux

(µm

ol/k

g/m

in)

Whole body

*

controlstrauma

-1

-0,5

0

0,5

1

1,5

2

2,5

3

breakdownsynthesis

balance

leuc

ine

flux

(µm

ol/k

g/m

in)

Whole body

**

Mansoor O, PNAS 1996

freeAA

Synthesis (300 g/d)

Intake

Proteolysis (300 g/d)

Oxidation

Intestine(40 %/d)

Kidney(30 %/d)

Skin(15 %/d)

~ 100 g/d

~ 50 g/d

Schematic overview of tissue-specific protein turnover (% per day) in humans

Muscle(2 %/d)

Liver(25 %/d)

?

controlstrauma

Mansoor O, AJP 1997

-1

-0,5

0

0,5

1

1,5

2

2,5

3

breakdownsynthesis

balance

leuc

ine

flux

(µm

ol/k

g/m

in)

Whole body

**

05

101520253035

fibrinogen albumin

liver*

*

%

0

0,5

1

1,5

2

2,5 muscle

*%

freeAA

Muscle

Synthesis

Proteolysis

Oxidation

Intestine

Kidney

Skin

Schematic overview of tissue-specific protein turnover in humans

Liver AcutePhaseProteins

freeAA

Muscle(2 %/d)

Proteolysis

Oxidation

Intestine

Kidney

Skin


Synthesis

Muscle

AcutePhaseProteins

Liver

ANABOLIC RESISTANCE

Muscle(2 %/d)

Synthesis

Intake

Proteolysis

Oxidation

Intestine

Kidney

Skin


Muscle

AcutePhaseProteins

Liver

freeAA

ANABOLIC RESISTANCE

Message

• En situation d’agression, le muscle est en situation hypercatabolique par activation du système protéasome Ubiquitine-ATP dépendant

• Cependant, il existe une forte réduction de la synthèse des protéines musculaires qui définit la « résistance anabolique » et qui empêche la récupération des protéines dégradées

MÉCANISMES DE LA RÉSISTANCE ANABOLIQUE

MuscleProteins

AAAA AAAA

ProteolysisSynthesis

10

0

2

4

6

8

AS

R (

mg/

j)

0

0.2

0.4

0.6

0.8

1

nmol

tyro

sine

/mg

prot

/h

Protein Balance

0

Postabsorptive

Postabsorptive protein balancein skeletal muscle

AAAA AAAA

10

0

2

4

6

8*

AS

R (

mg/

j)

*

0

0.2

0.4

0.6

0.8

1

nmol

tyro

sine

/mg

prot

/hPostprandial

0

MuscleProteins

Postabsorptive


Postprandial protein balancein skeletal muscle

Protein Balance

ProteinAAAA AAAA


10

0

2

4

6

8*

AS

R (

mg/

j) *

0

0.2

0.4

0.6

0.8

1

nmol

tyro

sine

/mg

prot

/h

postabsorptif

postprandial

SarcopSarcopSarcopSarcopéééénienienienie

Perte de l’effet anabolique du repas

=

ProteinAAAA AAAA

ProtéolyseSynthèse

10

0

2

4

6

8*

AS

R (

mg/

j) *

0

0.2

0.4

0.6

0.8

1

nmol

tyro

sine

/mg

prot

/h

postabsorptif

postprandial

CachexieCachexieCachexieCachexie

Perte de l’effet anabolique et anticatabolique du repas

Leu

Gly

Hi s

Met

Phe

Tyr

Gln

His

Pro

L ys

CTGCTAAGTCGCTCTACGTTAGGGCGACGAT TCAGCG

A

AT

CG

GCGT

TU

U

C CGC

CC

C

C

TT

T

G

GG GGU U

UU

T

T

TT

U U

G

G

GGU

AA

T

C

T G

T

TUrRNA

nucleus

DNA

mRNA

protein

transcription

translation

tRNA -Lys

t RNA - Glnt RNA -Asp

tRNA -Leu

t RNA -Gly

tRNA -His

tRNA -Val

tRNA -Ile

t RNA tRNA

tRNAtRNA

GCG

Leu

Gly

Hi s

Met

Phe

Tyr

Gln

His

Pro

L ys

CTGCTAAGTCGCTCTACGTTAGGGCGACGAT TCAGCG

A

AT

CG

GCGT

TU

U

C CGC

CC

C

C

TT

T

G

GG GGU U

UU

T

T

TT

U U

G

G

GGU

AA

T

C

T G

T

TUrRNA

nucleus

DNA

mRNA

protein

transcription

translation

tRNA -Lys

t RNA - Glnt RNA -Asp

tRNA -Leu

t RNA -Gly

tRNA -His

tRNA -Val

tRNA -Ile

t RNA tRNA

tRNAtRNA

GCG

Lys

Leu

Glu

Gly

ArgPhePhe

Leu IleGlutRNA tRNA

tRNA

Energysubstrates

AA

SignallingFactors

INSULIN

Glass DJ, Int J Biochem Cell Biol 2005

AAEn.

INSULIN CYTOKINES

Glass DJ, Int J Biochem Cell Biol 2005

AAEn. ?

ALTÉRATION DE LA RÉPONSE PROTÉIQUE POSTPRANDIALE

Availability Muscle

AA

Intake

Meal

CarbohydratesFat

Proteins

Absorption

AAInsulin

Postprandial anabolic resistance?

A lower anabolic response to nutrients intake in muscle may be the consequence of alterations in:

Intake

CarbohydratesFat

Proteins

Protein intake … g/kg/d ?

• impact of disease?• protein / energy ratio?


Meal

Nitrogen balance in hospitalized elderly patients: the more is the better?

1.06

Gaillard C, JAGS 2008

Safe protein intake is 1.3-1.6 g/kg/d(mean + 2SD), similar for men and women

Intake

Meal

CarbohydratesFat

Proteins

Absorption


A lower anabolic response to meal intake in muscle may be the consequence of alterations in:

AA

CirculatingProteins

[insulin]

AA

AA

Muscle

Liver

Inflammatoryproteins

Splanchnic extraction of AA

?intestineProteins

Intake

Meal

CarbohydratesFat

Proteins

Absorption



Boirie, Am J Clin Nutr 1997Volpi , Am J Physiol 1999

Spl

anch

nic

extr

actio

n %

0

20

40

60

80*

Spl

anch

nic

extr

actio

n %

0

10

20

30

40

50

60

Phenylalanine

*

Leucine

AA

YoungElderly

Splanchnic extraction of AA

Availability Muscle

AA

Intake

Meal

CarbohydratesFat

Proteins

Absorption

AA

Insulin



AA

InsulinAA

Translation initiation

PI3K

Akt

GSK3

EIF2B 4EBP1

mTOR

S6K

Aging : defect in the regulation of mTOR signalling pathw ay

by amino acids Leucine resistanceby insulin Insulin resistance

Dardevet, J Nutr 2000Cuthberson, FASEB J 2005

Guillet, FASEB J 2004Rasmussen, FASEB J 2006

Message

• Les voies de signalisation de la synthèse protéique sont finement contrôlées par l’insuline et les acides aminés pour l’activation de la traduction protéique

• L’agression (cytokines) réduit la stimulation postprandiale de la synthèse et accélère le programme protéolytique (protéasome) aboutissant à l’atrophie musculaire

• La résistance anabolique a plusieurs origines : apports protéino-énergétiques, passage splanchnique ? insulinorésistance ?

IDENTIFICATION DE CIBLES POTENTIELLES ET STRATÉGIES D’ACTION

Meal

Anabolic

resistance

Physiological situation

Muscle

Anabolism

Threshold

Aging or catabolic state

Anabolic resistance in muscle loss situations

Anabolic stimulators

time

Meal


Anabolicresponse

Meal


Meal

Anabolic response

Meal

Anabolicresistance

Anabolic treshold

Increased anabolic threshold

2 strategies

�� to reduce muscle anabolic threshold

�� to increase the availability of anabolic stimulator s

Meal

Anabolic stimulators Anabolic

stimulators

Meal

Meal

Physiological situation Aging or catabolic state


Oxidative stress/Inflammation

AntioxidantsAnti-inflammatory

nutrients

Restore Muscle Anabolic Sensitivity

Improving muscle sensitivity to anabolic factors?

Anabolic resistance may be induced by chronic low grade inflammation and

prevented by ibuprofen administration

*

2.5

3.0

3.5

4.0

4.5

5.0

5.5PostabsorptivePostprandial

No Inf Low Grade Inf

Pro

tein

syn

thes

is (

%/d

)

+ Ibuprofen

*

3.03.13.23.33.43.53.63.73.8

IbuprofenCT

Mus

cle

Mas

s (g

) *+10.6%

Rieu I, J Physiol 2009

Smith GI, Am J Clin Nutr 2011

Muscle proteinsynthesis

+ INS

Signaling pathwaysfor the initiation ofProtein synthesis

+ INS

+ INS

Muscle protein synthesis of old rats fed a control die t (OC), a high-oleate diet (HFO) or a high-palmitate diet (HF P)

+ INS

+ INS

+ INS

+ INS

+ INS

+ INS

Tardif N, Clin Nutr 2011

Muscle proteinsynthesis

Signaling pathwaysfor the initiation ofprotein synthesis

Control Oleate Palmitate

Control Oleate Palmitate

Insulin AA


PI3K

Akt

GSK3

EIF2 4EBP1

mTOR

S6K

MUSCLE PROTEIN SYNTHESIS

↓↓↓↓ Inflammation↓↓↓↓ Oxidative stress

n-3 PUFAOleate

Antioxidants

Meal

Anabolic

resistance


Others?



Other mechanisms of anabolic resistance?

Lipotoxicity

Postabsorptive

Insulin clamp

R2 = 0,42

0

0.02

0.04

0.06

0.08

0.10

0.12

0 10 20 30 40 50Mus

cle

prot

ein

synt

hesi

s (%

/h)

Fat mass (kg)

Guillet C, JCEM 2009Guillet C, Curr Opin Clin Nutr Metab Care 2011

Muscle Mitochondrial Protein synthesis (%/h)

Adiposity may be deleterious for muscle protein synthesis

Non-OB OB

Response to high-fat feeding of total and mitochondrial protein synthesis

Masgrau A, J Physiol 2012 (in press)

Mixed muscle protein Mitochondrial protein

Muscle cell

Insulin

Glucose entry & storage

Akt

Initiation of protein translation

Protein synthesisProtein anabolicresistance

Insulin resistance

Tardif N, Aging Cell submitted

eIF2a controls the inhibition of skeletal muscle protein synthesis driven by ceramides in response

to diet-induced obesity in sarcopenic old rats

EIF2αααα phosphorylation

Saturated FA

Ceramides

Insulin AA


PI3K

Akt

GSK3

EIF2 4EBP1

mTOR

S6K

Lipotoxicity and muscle anabolic response


Saturated FA(Palmitate)

Ceramide

EIF2αααα

Das SK, Science 2011Fearon K, NEJM 2011

Lipolysis (AGTL) inactivation in tumor bearing animals prevents muscle cachexia despite inflammation

inhibition of lipolysis may help to prevent cachexia in patients with cancer or other chronic diseases

Meal

Anabolic

resistance


Others?

Nutrition, Metabolisms and Muscle Loss



Modulators of muscle anabolic resistance?

Vitamin D deficiency

Lipotoxicity/Insulin Resistance

Vitamin D & muscle

� Vitamin D deficiency

Direct role of vitamin D on skeletal muscle mass & function

Direct role of vitamin D on skeletal muscle mass & function

- Muscle fiber atrophy - Loss of physical performance- Increased risk of fall

� Vitamin D supplementation

(Smith and Stern, 1967; Pfeifer et al., 2009;

Bischoff-Ferrari et al., 2009; Sato et al., 2005)

(Prineas et al., 1965; Dhesi et al., 2002; Snijder et al., 2006)

- Improved muscle mass & function

1,25(OH)2-vitamin D3 combined to anabolic factors increases protein synthesis in differentiated C2C12

skeletal muscle cells

+Insulin+Insulin

+Leucine+Leucinea

b bc

0

,25

,5

,75

1

1,25

1,5

1,75

2

2,25

Insulin + leucine

Vitamin D (nM)

+ -

0 0 10

+

10

FS

R (

%/h

)

Muscle cells protein synthesis

-

Insulin AA


PI3K

Akt

GSK3

EIF2 4EBP1

mTOR

S6K

Vitamin D: a multi-effect nutrient on muscle anabol ism?

Saturated FA(Palmitate)

Ceramide


Vitamin D

Vit D

Vit D

VDR

Vit D-response element

Nucleus

?

+

Meal

Anabolic

resistance


Oxidative stress/InflammationLipotoxicity/Insulin Resistance

Immobilization/Chronic Diseases



Insulin AA


PI3K

Akt

GSK3

EIF2 4EBP1

mTOR

S6K

Immobilization and chronic diseases

Ceramide


⇓⇓⇓⇓ Vitamin D

Vit D

Vit D

Stressfactors

Deficiency

Intramyocellularlipid derivatives

accumulation

Insulinresistance

Oxidative stress

Meal

Anabolic

resistance


Oxidative stress/InflammationLipotoxicity/Insulin Resistance

Impaired muscle blood flow?



Timmerman KL, Diabetes 2010 & AJCN 2012

Insulin AminoAcids


Nutritional interactionsAnabolic

substratesAnti-anabolic

substrates

-

Negative regulatorsInhibitory effects

saturated FA

Ceramide

testosterone cytokines

exercise immobilization

+

Pos

itive

reg

ulat

ors

Per

mis

sive

effe

cts

n-3 PUFA

antioxidants

Vitamin D

Message

• La résistance anabolique peut être modulée positivement ou négativement par des médiateurs nutritionnels (AA, AGS, AGMI, AGPI, céramides) , hormonaux (insuline, IGF1, testostérone) ou vasculaires (NO) pour stimuler la synthèse protéique

Meal


Anabolic responseover baseline

Meal

Temporal changes in anabolic threshold?

Sedentarity

Inflammation(acute disease)

LipotoxicityInsulin-R

(Fat feeding)

Oxidative Stress

LOWERSENSITIVITY

Meal

Anabolic

resistance


• Increased availability of anabolic stimulators

• Acting on the diet and the determinants of digestion rate• Modulating splanchnic metabolism in physiopathologi cal situations

How ?

Acting on the diet and the determinants of postprandial protein utilization

• Increase protein intake?

• Specific AA supplementation?

• Improve AA bioavailability:– Change the distribution of protein intake?– Use proteins of different digestion rate?

• Physical exercise?

Protein pulse-feeding pattern (chrononutrition)

Lunch

Breakfast

Snack

DinnerBreakfastDinner

Lunch (80%)

Spread-feeding Pulse-feeding Pulse feeding=�� nitrogen

retention in the elderly

Meat with healthy dentitionMeat with chewing deficiency

Time, min0

50

100

150

200

250

0 100 200 300 400 500

�� in

pla

sma

leuc

ine,

µM

Fast proteins (Whey)Slow proteins (Casein)

Protein digestion rate (fast/slow proteins concept)

Fast proteins=�� postprandial

WB protein anabolismin the elderly

Boirie et al., PNAS 1997Remond et al., Am. J. Clin. Nutr. 2007

Arnal et al. Am J Clin Nutr 1999 & J Nutr 2002

Pennings B, Am J Clin Nutr 2011

CASCAS-H

WHEY

Fast and high!

Irving BA, Aging Res Rev 2012

Physical exercise acts as snesitizer and an anaboli c signal

Physical exercise potentiates the anabolic impact of amino acids

Biolo G, J Clin Invest 1995

45

30

15

0

-15

-30

a

b

Rest ExerciseRest+ AA

c

Exercise+ AAA

A b

alan

ce a

ccro

ss th

e le

g

Kim KH, JAGS 2012

Tieland M, JAMDA 2012

synthesis breakdown

Looking for the best synergistic combination to improve protein gain

NUTRITIONPHYSICAL ACTIVITY

HORMONES DRUGS

Message

• La résistance anabolique peut être réduite par une combinaison de médiateurs nutritionnels, hormonaux ou vasculaires en association avec une activité physique

• Ces stratégies peuvent stimuler la synthèse protéique à court terme mais les effets à long terme sont peu connus : nécessité d’études randomisées vs. contrôles

Many research perspectives

Musclemetabolism

Proteinsynthesis

Proteinbreakdown

Apoptosis

Regeneration

Nutrition

Hormones

Activity

InflammationDiseases

From Budford TW, Ageing Res Rev 2010

Human Nutrition UnitMetabolism & Health

MERCI !

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