Anabolic resistance: a road map to malnutrition

The Danish Society of Clinical Nutrition
Annual Clinical Nutrition Meeting 2012
Copenhagen, Denmark – 8 June 2012
Anabolic resistance:
a road map to malnutrition
Gianni Biolo
Department of Medical Science - University of Trieste
Department of Internal Medicine - AOUTS
Trieste - Italy

g
30
25
20
15
10
J Coll Gen Pract. 1963
5
0
Daily nitrogen intake
Daily nitrogen excretion
Nitrogen balance of a fractured patient of 34 years receiving 1.5 g protein/kg/day
(The Disturbance of Metabolism Produced by Bony and non-Bony Injury. Biochem J. 1930)

EFFECTS OF AMINO ACID INFUSION ON SKELETAL MUSCLE
PROTEIN BALANCE IN SEVERELY BURNED PATIENTS
MUSCLE PROTEIN BALANCE
phenylalanine nmol/min/100 ml
80
0
-80
Biolo & Wolfe, Clinical Nutrition (abstract) 2001
Healthy
volunteers
*
Burned
patients
Postabsorptive state Amino acid infusion
*, P

F V,A
MODEL OF LEG MUSCLE
AMINO ACID KINETICS
THE ROLE OF TRANSMEMBRANE AMINO ACID
TRANSPORT KINETICS IN ANABOLIC RESISTANCE
A
V
F IN
F OUT
F M,A
F V,M
M
F 0,M
F M,0
JPEN 1992
AJPENDO 1995

F M,A / F IN
F V,A
MODEL OF LEG MUSCLE
AMINO ACID KINETICS
A
V
F IN
F OUT
impaired ability of transport systems
and
increased shunting of leg blood flow from artery to vein
through non-nutritive routes
F M,A
F V,M
M
F 0,M
F M,0
JPEN 1992
AJPENDO 1995

F V,A
MODEL OF LEG MUSCLE
AMINO ACID KINETICS
A
V
F IN
F OUT
F M,A
F V,M
M
F 0,M
F M,0
JPEN 1992
AJPENDO 1995
“Strategies to decrease anabolic resistance should include
attempts to increase microvascular, nutritive muscle blood
flow.”

J. Clin. Invest. 95:811-819, 1995
MUSCLE PROTEIN SYNTHESIS
*
*
nmol /min x 100 ml leg vol.
800
700
600
500
400
300
200
100
0
ml/min/100ml leg vol.
INWARD AMINO ACID TRANSPORT
*
*
(F (FM,A) M,A)
PHE LEU LYS ALA
BASAL INSULIN
LEG BLOOD FLOW
5
4
3
2
1
0
*
BAS INS
*
*

RELATIONSHIPS BETWEEN INSULIN-MEDIATED STIMULATION OF
MUSCLE BLOOD FLOW AND PROTEIN SYNTHESIS
(leg or forearm A-V balance technique combined with stable isotopes)
Mean changes in muscle protein protein synthesis
(nmol/min/100ml leg vol)
500
400
300
200
100
0
R 2 = 0.9318
-20
-100
0 20 40 60
Mean changes in leg blood flow
(ml/min/100ml leg vol)
80
Moeller-Loswick et al., AJP 1994
Moeller-Loswick et al., AJP 1995
Zanetti et al., Cl Science 1999
Tessari et al., JCI 1991
Arfdisson et al., AJP 1991
Meek et al., Diabetes 1998
Denne et al., AJP 1991
Biolo et al., JCI 1995
Gelfand & Barrett, JCI 1987
Louard et al., JCI 1992
Biolo et al, Diabetes 1999

MUSCLE PROTEIN SYNTHESIS
ml/min/100ml leg vol.
LEG BLOOD FLOW
8
6
4
2
0
*
BAS INS

µµmol · kg-1 · min-1 µµmol · kg-1 · min-1 EFFECT OF INSULIN-MEDIATED GLUCOSE CONTROL ON
1.2
0.8
0.4
0
Whole body
*
Phe Ra from
proteolysis
PROTEIN KINETICS
-1 -1
nmol · 100cc-1 · min- nmol · 100cc-1 · min- 60
40
20
0
Skeletal muscle
*
Phe Rd to
Protein
synthesis
Phe Ra from
proteolysis
24-h HYPERGLYCEMIA (~180 mg/dl) 24-h EUGLYCEMIA (~110 mg/dl)
CANCER PATIENTS AFTER MAJOR ABDOMINAL SURGERY ON TPN

Am J Physiol. 1995 Mar;268(3 Pt 1):E514-20.
Increased rates of muscle protein turnover and amino acid transport after resistance exercise in humans.
Biolo G, Maggi SP, Williams BD, Tipton KD, Wolfe RR.
Department of Internal Medicine, University of Texas Medical Branch, Galveston.
RELATIONSHIP BETWEEN LEG BLOOD FLOW (BF) AND MUSCLE
PROTEIN SYNTHESIS (FSR) AFTER EXERCISE
FSR (% per hour)
0,20
0,16
0,12
0,08
0,04
R 2 = 0.52
1 2 3 4 5 6 7 8
BF (ml/min x 100ml leg vol.)
Exercise increases microvascular, nutritive muscle blood flow

AJPENDO 1997
BASAL
nmol /min x 100 ml leg vol.
% per hour
1200
1000
800
600
400
200
0
0,18
0,15
0,12
0,09
0,06
0,03
0,00
HYPERAMINOACIDEMIA
AT REST
HYPERAMINOACIDEMIA
AFTER EXERCISE
INWARD AMINO ACID TRANSPORT
(FM,A) (FM,A) (FM,A)
PHE LEU LYS ALA
FRACTIONAL SYNTHESIS RATE
OF MUSCLE PROTEIN
Fractional Synthesis rate
(% per hour)
0.20
0.16
0.12
0.08
0.04
0.00
F V,A V,A V,A
A
V
F IN
F OUT
F M,A
F V,M
M
F 0,M
F M,0
R 2 R = 0.61
2 = 0.61
0 200 400 600 800 1000 1200
Inward Transport (nmol/min x 100 ml)

nmol PHE/min x 100 ml leg vol.
Regulation of muscle protein balace in the fasting
and postprandial states at rest and after exercise
50
40
30
20
10
0
-10
-20
-30
REST
POST-EXERCISE RECOVERY
FASTING
*: P

Resistance training to counteract the catabolism of a
low-protein diet and reduce the malnutrition-inflammation complex
syndrome of chronic kidney disease
Castaneda et al. Ann Int Med 2001; Am J Kidney Dis 2004
Patients with chronic kidney
disease, not on dialysis therapy
n = 26
Randomized, Controlled Trial
CRP
(mg/L) changes
p

EXERCISE
INACTIVITY
?
INCREASED
ANABOLIC
EFFICIENCY
ANABOLIC
RESISTANCE

anabolic resistance
CONTROLS
CIRRHOTIC PATIENTS
CHANGES VERSUS BASELINE
AFTER INSULIN, GLUCOSE AND AMINO ACID INFUSION

Metabolic Effects of Very Low Calorie
Weight Reduction Diets
L.J. Hoffer, B.R. Bistrian, V.R. Young, G.L. Blackburn, and D.E. Matthews
J Clin Invest 1984
501 ± 39 kcal
0.8 g protein/kg ideal BW
559 ± 79 kcal
1.5 g protein/kg ideal BW
WEIGHT
NITROGEN
BALANCE
LOSS p = NS p < 0.01

CHRONIC CONDITIONS WITH ANABOLIC RESISTANCE
Sarcopenia of aging
Cancer cachexia
Chronic renal failure
Rheumatoid arthritis
Osteoarthritis
HIV/AIDS
COPD
Anorexia
Male hypogonadism
Obesity (weight loss)
Corticosteroid administration
(transplant, autoimmune
disease)
Coronary artery disease
Congestive heart failure
Liver Cirrhosis
Type 1 and 2 diebetes mellitus
Hip fracture
Disuse atrophy
(spinal cord injury, bed rest,
microgravity)

MUSCLE MASS
NORMAL
NUTRITIONAL
STATUS
MUSCLE WASTING
IN CHRONIC DISEASES AND AGING
TIME
ACUTE
STRESS
COMPLICATIONS
MORTALITY

PREOPERATIVE INSULIN RESISTANCE AND THE IMPACT OF FEEDING ON POSTOPERATIVE
Delta in phenylalanine protein balance
(micromo/kg/min) expressed expressed as
differences fed values minus fast
7
6
5
4
3
PROTEIN BALANCE. A STABLE ISOTOPE STUDY
Francesco Donatelli, Davide Corbella, Marta Di Nicola, Franco Carli, Luca Lorini, Roberto Fumagalli, Gianni Biolo.
Ospedali Riuniti di Bergamo, Italy; McGill University Health Centre, Montreal, Quebec, Canada; University of Trieste, Italy
J Clin Endocrinol Metab 2011
2
1
0
ANABOLIC EFFICIENCY OF FEEDING
Normal insulin
sensititivity
Preoperative insulin
resistance
PRE-SURGERY POST-SURGERY
Well-nourished patients with coronary artery disease
Elective coronary by-pass surgery
*, p=0.04, surgery effect of; p=0.002, group effect; p

AGING
HORMONE
DEFICIENCY
OR EXCESS
Sarcopenia of aging
Cancer cachexia
Chronic renal failure
Rheumatoid arthritis
Osteoarthritis
HIV/AIDS
COPD
Anorexia
Male hypogonadism
Obesity (weight loss)
LOW PROTEIN – ENERGY
INTAKE
MECHANISMS OF ANABOLIC RESISTANCE
IN CHRONIC CONDITIONS
CHRONIC CONDITIONS WITH ANABOLIC RESISTANCE
HYPOPERFUSION
HYPOXIA
Corticosteroid administration
(transplant, autoimmune
disease)
Coronary artery disease
Congestive heart failure
Liver Cirrhosis
Type 1 and 2 diebetes mellitus
Hip fracture
Disuse atrophy
(spinal cord injury, denervation,
bed rest, microgravity)
OXIDATIVE STRESS
AND
CHRONIC
INFLAMMATION
CANCER
CACHECTIC
FACTORS
LOW PHYSICAL
ACTIVITY

Inactivity Amplifies the Catabolic Response of
Skeletal Muscle to Cortisol
Ferrando et al., J Clin Endocrinol & Metab, 1999
Ambulatory
5-days
nmol phenylalanine/
/min/100 ml leg vol.
12-h hydrocortisone infusion
(120 microg/kg/h)
0
-25
-50
-75
Bed rest
14-days
MUSCLE PROTEIN BALANCE
P

percent
50
25
0
Meal-induced
stimulation of protein synthesis
* *
AMB BR AMB BR
Eucaloric diet Hypocaloric diet
micromol leucine/kh/min
kg
0.30
0.25
0.20
0.15
0.2
-0.2
-0.6
-1
-1.4
CHANGES IN
LEAN MASS (DEXA)
Eucaloric
Ambulatory
Hypocaloric
Ambulatory
Eucaloric
Hypocaloric
Bed Rest
Bed Rest
Protein catabolism
in the fasting state
AMB BR AMB BR
Eucaloric diet Hypocaloric diet
*
*

MALNUTRITION IN PATIENTS WITH
CANCER OR CHRONIC DISEASES
Anabolic resistance → muscle atrophy
CACHEXIA
ANOREXIA
SARCOPENIC OBESITY
ADEQUATE OR INCREASED
NUTRIENT INTAKE

percent
40
30
20
10
0
PREVALENCE OF OBESITY IN COPD PATIENTS
Body Mass Index (kg/m 2 ) (BMI)
Low (30)
628 elderly patients with moderate to severe COPD (61% male)
Breyer et al., Clin Nutr 2009

(kJ/d)
6000
5750
5500
5250
5000
time effect
P = 0.02.
PHYSICAL
ACTIVITY
ENERGY
INTAKE
REDUCED ENERGY
REQUIREMENT
IN CANCER
PATIENTS
RMR Weight and Body Composition Changes during
and after Adjuvant Chemotherapy in Women
with Breast Cancer
J Clin Endocrinol Metab 2004
PRE CHEMOTHERAPY
2 wk 6 wk
43
kg 42
kg
23
41
40
39
time effect
P < 0.05
LEAN MASS
24
22
21
time effect
P < 0.05
FAT MASS

∆ (kg)
2
Changes in fat mass
(bioimpedence)
3 * §
1
0
Positive Energy Balance
Near-neutral Energy Balance
* , p

kg
STEPS/DAY
12000
10000
8000
6000
4000
2000
0
15
10
5
0
PRE
2 wk
TOTAL FAT
ml
Metabolic Responses to
Reduced Daily Steps in Healthy
Nonexercising Men
750
700
650
600
550
500
*, P

∆ (kg)
Changes in fat mass
(bioimpedence)
3 * §
2
1
0
Positive Energy Balance
Near-neutral Energy Balance
* , p

THE VICIOUS CYCLE OF SARCOPENIC OBESITY
INCREASED
FAT DEPOSITION
ABDOMINAL
PERIPHERAL
HEPATIC
MUSCULAR
POSITIVE
ENERGY
BALANCE
DECREASED
PHYSICAL
ACTIVITY
MUSCLE
ATROPHY
SYSTEMIC
INFLAMMATORY
RESPONSE
INSULIN
RESISTANCE
ANABOLIC
RESISTANCE
TO AMINO ACID
AND PROTEIN

2115
cancer patients
15%
obesity
15%
sarcopenic obesity
SURVIVAL

kg
100
80
60
CROSS-SECTIONAL STUDY
252 healthy subjects with normal body mass index, 35 to 65 years
BODY WEIGHT AND COMPOSITION IN AGING
40
20
0
BODY WEIGHT
LEAN MASS
FAT MASS
30 40 50 60 70
Age (years)
Clinica Medica – University of Trieste

Percent loss of lean body mass
Long-term bed-rest
(60 days) in healthy
female volunteers
WISE 2005 (Women
International Space Simulation
for Exploration)
0
-1
-2
-3
-4
-5
-6
-7
-8
-9
-10
ESA/CNES/NASA/CSA
BR
15 days
*
BR
31 days
Control
High-protein diet
BR
43 days
SKELETAL MUSCLE
ATROPHY (DEXA)
N = 8
N = 6
BR
60 days
Bed rest effect: p = 0.01; bed rest × diet interaction: p = 0.01
(repeated measures ANCOVA)
ADAPTATION
(20 days)
Ambulatory
conditions
Ambulatory
conditions
EXPERIMENTAL PERIOD
(60 days)
“Bed Rest”- Eucaloric diet
1 g protein / (kg · day)
non-protein calories to nitrogen ratio
134±3 kcal/g
“Bed Rest”- Eucaloric diet
1.4 g protein / (kg · day)
0.16 g BCAA / (kg · day)
non-protein calories to nitrogen ratio
86±2 kcal/g
REABILITATION
(20 days)
Ambulatory
conditions
Ambulatory
conditions
High-protein
CARDIAC ATROPHY (MRI)
Dorfman et al., J Appl Physiol 2007

Adjusting for covariates (age at inclusion, BMI at
inclusion, and BMD of the femoral neck at
inclusion) a significant (P < 0.05) difference was
seen in the response to training of bone mineral
density between the two groups.
Strength improvements from 6 to 24 wk, a
significant difference was apparent between
groups: nutrient group, 9±3% vs. control, 1±2% (P
< 0.05).

The majority of sick elderly patients require at
least 1 g protein/kg/day and around 30
kcal/kg/day of energy, depending on their
activity.

A 5-Year Cohort Study of the Effects of High Protein Intake on Lean Mass
and Bone Mineral Content in Elderly Postmenopausal Women
J Bone Miner Res. 2009
• relationship between baseline protein intake and lean mass and bone mineral
content (DEXA)
• 862 elderly postmenopausal women (mean age: 75 yrs)
• 5 years follow-up
6
4
2
0
whole body
lean mass
whole body
bone mineral density
Percent differences between the lowest (< 66 g/d), and the highest
(> 87 g/d) tertile of protein intake
A higher protein intake is associated with long term beneficial
effects on muscle mass and size and bone mass in elderly women

Whole-body Whole-body Whole-body protein loss
(kg (kg (kg / 2 weeks)
PROTEIN REQUIREMENT IN CRITICAL ILLNESS
AT ADEQUATE ENERGY INTAKE
Wolfe et al., Ann Surg 1983; Ishibashi et al., Crit Care Med 1998
0
-0.5
-1
-1.5
-2
Hoffer Am J Clin Nutr 2003
g protein / kg IBW per day
≈ 0.7 ≈ 1.0 ≈ 1.5 ≈ 2.2

Protein/amino acid
requirement
“1.3–1.5 g/kg ideal body weight
per day in conjunction with an
adequate energy supply”
(Grade B)
2009 ESPEN Guidelines

Medications and
nutraceuticals to
counteract
anabolic resistance

8 weeks supplementation
CLAMP = INSULIN+GLUCOSE+AMINO ACID INFUSION

90-day strength training increased muscle strength in elderly women. The inclusion of fish oil
supplementation caused greater improvements in muscle strength and functional capacity.
Fish
oil
Fish
oil
Fish
oil
Fish
oil

ANABOLIC
RESISTANCE
Critical illness
Chronic diseases
Aging
Inactivity
COUNTERACTING ANABOLIC RESISTANCE
• Increase microvascular, nutritive muscle blood
flow (exercise)
• Definition of optimal protein intake in each
condition
• Control of energy balance and fat mass
• Medications and nutraceuticals (?)

iolo@units.it
Department of Internal Medicine
Clinica Medica
Ospedale di Cattinara
University of Trieste
Trieste, Italy