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Résistance anabolique en situation d’agression
DESC de réanimation
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
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
Schematic overview of tissue-specific protein turnover in humans
Synthesis
Muscle
AcutePhaseProteins
Liver
ANABOLIC RESISTANCE
Muscle(2 %/d)
Synthesis
Intake
Proteolysis
Oxidation
Intestine
Kidney
Skin
Schematic overview of tissue-specific protein turnover in humans
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
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
ProteolysisSynthesis
Postprandial protein balancein skeletal muscle
Protein Balance
ProteinAAAA 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
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
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?
Postprandial anabolic resistance?
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
Postprandial anabolic resistance?
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
Postprandial anabolic resistance?
A lower anabolic response to meal intake in muscle may be the consequence of alterations in:
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
Postprandial anabolic resistance?
A lower anabolic response to meal intake in muscle may be the consequence of alterations in:
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 ?
Meal
Anabolic
resistance
Physiological situation
Muscle
Anabolism
Threshold
Aging or catabolic state
Anabolic resistance in muscle loss situations
Anabolic stimulators
time
Meal
Anabolic stimulators
Anabolicresponse
Meal
Anabolic stimulators
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
Anabolic stimulators
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
Translation initiation
PI3K
Akt
GSK3
EIF2 4EBP1
mTOR
S6K
MUSCLE PROTEIN SYNTHESIS
↓↓↓↓ Inflammation↓↓↓↓ Oxidative stress
n-3 PUFAOleate
Antioxidants
Meal
Anabolic
resistance
Oxidative stress/Inflammation
Others?
Physiological situation Aging or catabolic state
Anabolic stimulators
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
Translation initiation
PI3K
Akt
GSK3
EIF2 4EBP1
mTOR
S6K
Lipotoxicity and muscle anabolic response
MUSCLE PROTEIN SYNTHESIS
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
Oxidative stress/Inflammation
Others?
Nutrition, Metabolisms and Muscle Loss
Physiological situation Aging or catabolic state
Anabolic stimulators
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
Translation initiation
PI3K
Akt
GSK3
EIF2 4EBP1
mTOR
S6K
Vitamin D: a multi-effect nutrient on muscle anabol ism?
Saturated FA(Palmitate)
Ceramide
MUSCLE PROTEIN SYNTHESIS
Vitamin D
Vit D
Vit D
VDR
Vit D-response element
Nucleus
?
+
Meal
Anabolic
resistance
Physiological situation Aging or catabolic state
Oxidative stress/InflammationLipotoxicity/Insulin Resistance
Immobilization/Chronic Diseases
Anabolic stimulators
Modulators of muscle anabolic resistance?
Insulin AA
Translation initiation
PI3K
Akt
GSK3
EIF2 4EBP1
mTOR
S6K
Immobilization and chronic diseases
Ceramide
MUSCLE PROTEIN SYNTHESIS
⇓⇓⇓⇓ Vitamin D
Vit D
Vit D
Stressfactors
Deficiency
Intramyocellularlipid derivatives
accumulation
Insulinresistance
Oxidative stress
Meal
Anabolic
resistance
Physiological situation Aging or catabolic state
Oxidative stress/InflammationLipotoxicity/Insulin Resistance
Impaired muscle blood flow?
Anabolic stimulators
Modulators of muscle anabolic resistance?
Insulin AminoAcids
MUSCLE PROTEIN SYNTHESIS
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 stimulators
Anabolic responseover baseline
Meal
Temporal changes in anabolic threshold?
Sedentarity
Inflammation(acute disease)
LipotoxicityInsulin-R
(Fat feeding)
Oxidative Stress
LOWERSENSITIVITY
Meal
Anabolic
resistance
Anabolic stimulators
• 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?
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?
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
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
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