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Health and Exercise Science Research
Health and Exercise Science Research
Citrulline
1. Emphasize the importance of skeletal muscle size and quality for
healthy ageing.
2. Briefly review best protein nutrition practice for ageing muscles.
3. Evaluate the biological rationale and existing scientific evidence
base for emerging nutrients and/or neutraceuticals related to
promoting the health of ageing muscles.
4. Highlight gaps in research knowledge for the nutrition industry and
academia to exploit with regards to the active ageing market.
This presentation aims to…
Weak │ Promising │ Strong
Resveratrol Vitamin D
Arginine
Leucine Β-HMB Creatine
N-3 PUFA
Vitamins C and E
Sodium nitrate
Phosphatidic acid
Ursolic acid
Alcohol
Health and Exercise Science Research
The importance of muscle size and quality extends
beyond performance nutrition
Strength sports Aesthetics
PERFORMANCE
NUTRITION
ACTIVE
NUTRITION
HEALTH AND
WELLNESS
Power : mass
Healthy ageing Healthy weight loss Child growth ↓ Diabetes risk
Better choices, more often
↓ Obesity risk
Wolfe RR. The underappreciated role of muscle in health and disease. Am J Clin Nutr, 2006
Health and Exercise Science Research
Mu
scle
ma
ss (
AU
)
Age (years) 50
Healthy
Disuse-
accompanied
90
Ageing is associated with a gradual loss of skeletal muscle
mass that is exacerbated by periods of muscle disuse
“Threshold of disability”
Health and Exercise Science Research
65 YEARS OLD
PLUS
LATE 30’S &
EARLY 40S
MIDDLE AGED
The market space of active ageing extends beyond 65
years plus
MUSCLE
RECONDITIONING
Health and Exercise Science Research
6
“The progressive decline in skeletal muscle mass (myopenia) and strength (dynapenia) that
predisposes reduced muscle function with advancing age”
Report of the International working group on sarcopenia
Fielding et al 2011 Age and Ageing 12(4): 249-256
What is the definition of sarcopenia?
Health and Exercise Science Research
The cause of sarcopenia is clearly multifactorial,
interconnected and complex
Exercise
Insulin Resistance/Blood Flow
Injury/Illness
DNA Damage/Apoptosisis
Hormonal Changes
Anabolic Resistance
Inactivity
Motor Units
Oxidative Stress
Nutrition
Satellite Cells Low grade inflammation
AGE 25 AGE 65
Morley 2012 Fam Practice
Health and Exercise Science Research
What is muscle protein synthesis and why should the nutrition
industry care in terms of healthy ageing
Amino Acids
BLOOD
Amino Acids
MUSCLE PROTEINS
(MYOFIBRILLAR AND MITOCHONDRIAL)
MPS MPB MUSCLE
Mitochondrial Proteins
PB
PS
Collagen Proteins
PB PS
PS
Health and Exercise Science Research
0 5 10 15 20 25 30 35 40 450.00
0.05
0.10
0.15Young
Elderly
Dose of EAA
** **
Myofibrillar protein FSR (%/h)
Cuthbertson et al. 2005 FASEB J
1
2 3
The response of muscle protein synthesis to amino acid
feeding is impaired in older adults
Health and Exercise Science Research
10
Low-grade inflammation impairs the stimulation of muscle
protein synthesis in response to food intake
• 2 groups of rats: low grade inflamed (LGI)
group and a control non-inflamed (NI) group
• Muscle (gastrocnemius) protein synthesis
• Fasted and fed state
Non inflammed Low grade inflammed
0
2
4
6Fasted Fed
a
b
a a
Muscle protein synthesis (%/day)
Balage et al. 2010 J Nutr Biochemistry
Health and Exercise Science Research
INGESTED PROTEIN
SOURCE
The magnitude of the “muscle protein synthetic” response to
ingested protein is regulated on several levels of physiology
MUSCLE PROTEIN SYNTHESIS
Myofibrillar │ mitochondrial │ collagen
3. Amino acid uptake by skeletal
muscle
Amino acid transporters
Leucine mTORC1
p70S6K1 4E-BP1
MAP4K
LAT1
4. Anabolic cell
signaling
a. Protein digestibility
b. Amino acid absorption kinetics
1. Blood amino acid
availability
c. Splanchnic
retention of
amino acids
a. Blood flow
b. Capillary recruitment (via insulin)
c. Microvascular perfusion
2. Amino acid delivery to skeletal
muscle
↑ Insulin response
11
Health and Exercise Science Research
Witard et al 2014 Am J Clin Nutr
Dose of whey protein (g)
Muscle protein synthesis (%/h)
0 10 20 40
0.00
0.02
0.04
0.06
0.08
0.10
aa
bb
0 10 20 40
0.00
0.03
0.05
0.08
0.10 c
b
aa
Yang et al 2012 Br J Nutr
Dose of whey protein (g)
Muscle protein synthesis (%/h)
The ‘optimum’ protein dose for maximal stimulation of
muscle protein synthesis increases with advancing age
Health and Exercise Science Research
The potential drawback associated with recommending
increased daily protein intakes in older adults
Leidy et al. 2007 Obesity
High altitude
exposure
Anorexia
Reduced energy intake
↓ appetite regulating
hormones
15% 30%
0
20
40
60
80
100
15% 30%
0
20
40
60
80
100
Hunger (VAS: 1-100) Fullness (VAS: 1-100)
Protein content of diet
*
*
─ Older (64 years old) women
─ 9 wk dietary control
─ En% protein - 15% vs 30%
Health and Exercise Science Research
Maximise anabolic potency Enhance anabolic sensitivity
Daily protein intake Meal-by-meal
protein intake
Prior exercise Coingesting other nutrients
Anti-inflamm.
nutrients Vitamin
D
Optimising the response of MPS
Nitrates Neutra-
ceuticals Alcohol
How can industry and academia collaborate to
overcome age-related anabolic resistance?
β-HMB
Creatine Antioxidants Leucine
Ca+ Free acid
Arginine
Citrulline
Sodium nitrate
Phosphatidic acid
Ursolic
acid
Curcumin
Vitamins C and E
N-3 PUFA
Resveratrol
Health and Exercise Science Research
Fish oil supplementation potentiates the response of muscle
protein synthesis to simulated feeding in older adults
Basal Fed Basal Fed
0.00
0.02
0.04
0.06
0.08
0.10
Mixed muscle protein synthesis (%/h)
Before n-3 PUFA
supplementation
After n-3 PUFA
supplementation
* • Healthy active young men (n=5) and women (n=4)
• 8 weeks of fish oil derived n-3 PUFA supplementation
- 4 g/day fish oil capsules
- 1.86 g/day EPA and 1.50 g/day DHA
• Basal and stimulated measurements of MPS
Smith et al. 2011 Clinical Science,
Health and Exercise Science Research
Kalmorat & Gray 2013 Biochem and Biophys
• C2C12 myotubes
• Incubated with ethanol (control),
EPA or DHA
• Stimulated by leucine
• Protein synthesis and protein
breakdown
EPA is the “anabolic” component of fish oils
Protein synthesis rate
(Phenylalanine kinetics)
Control EPA DHA
0.0
0.5
1.0
1.5*
Protein breakdown rate
(Phenylalanine kinetics)
Control EPA DHA
0
5
10
15
20
*
Health and Exercise Science Research
Resveratrol may protect against the age-related loss of
muscle loss via anti-inflammatory properties
Wang et al. 2014 Int Immunopharmacology
• C2C12 myotubes (a mouse cell line)
• Treated with TNF-α
• Incubated with or without resveratrol
• Direct and indirect markers of
muscle atrophy
0
5
10
15
20
25
TNF-α:
Resveratrol:
_ +
_ _
_
+
+
+
Myotube diameter (μm)
Health and Exercise Science Research
Myotubes Myoblasts Osteoblasts
0
20
40
60
80Pre
Post
Tracer uptake of 25(OH)D
Abboud et al. 2013 Endocrinology
Vitamin D is taken up and stored in skeletal muscle cells
*
*
Health and Exercise Science Research
Control Ins+Leu Ins+Leu+VitD
0.0
20.0
40.0
60.0
80.0
100.0
120.0
140.0
a
b
c
Salles et al. 2013 Mol. Nutr. Food Res
Protein synthesis rate
(A.U.)
• C2C12 myotubes
• Control (unstimulated cells)
• Ins+Leu (stimulated with leucine and insulin only)
• Ins+Leu+VitD (cultured in 1,25(OH)2D3 for 72 h)
Vitamin D has been shown to enhance the MPS response
to an anabolic stimulus
Health and Exercise Science Research
Curcumin may protect against muscle loss in older adults
by reducing muscle inflammation and oxidative stress
Ono et al. 2015 Exp Phys
• Old mice injected with
streptozotocin to induce T1D
• 2 weeks of diet with or without
curcumin (1500 mg· kg-1 · day)
• Measurements of skeletal muscle
weight and myocyte cross-
sectional area
Con
trol
Con
trol+
Cur
cum
inT1D
T1D+C
urcu
min
0
50
100
150
200
250
a a
bc
Rectus femoris weight (mg)
Health and Exercise Science Research
INGESTED PROTEIN SOURCE
Biological rationale behind the potential for nitrates to enhance
the MPS response
(MYOFIBRILLAR) MUSCLE PROTEIN SYNTHESIS
a) Protein digestibility b) Amino acid absorption kinetics
1. Blood amino acid availability
2. Amino acid delivery to skeletal muscle
3. Amino acid uptake by skeletal muscle
mTORC1
p70S6K1 4E-BP1
MAP4K
LAT1
a) Blood flow b) Capillary recruitment c) Microvascular perfusion
Amino acid transporters
Leucine
4. Anabolic cell signaling
Health and Exercise Science Research
Dietary nitrate supplementation
(MYOFIBRILLAR) MUSCLE PROTEIN SYNTHESIS
↑ Nitric oxide availability
↑ insulin delivery
↑ muscle perfusion and capillary action
Rationale behind the potential for nitrates (arginine, citrulline
and sodium nitrate) to enhance the MPS response
Health and Exercise Science Research
Kouw et al. 2016 Am J Phys,
Sodium nitrate and protein coingestion: findings from
pharmacological and physiologically relevant studies
0.00
0.02
0.04
0.06
0.08
*
Fasted Protein Protein +
sodium nitrate
Myofibrillar-MPS
Dillon et al. 2011 Am J Phys,
Faste
d yo
ung
Faste
d old
AA +
SNP y
g
AA +
SNP o
ld
0.00
0.02
0.04
0.06
0.08
0.10
*Mixed-MPS
Health and Exercise Science Research
Maximise anabolic potency Enhance anabolic sensitivity
Daily protein intake Meal-by-meal
protein intake
Prior exercise Coingesting other nutrients
Anti-inflamm.
nutrients Vitamin
D
Optimising the response of MPS
Nitrates Neutra-
ceuticals Alcohol
Take home messages:
Optimising nutrition for older muscles
β-HMB
Creatine Antioxidants Leucine
Ca+ Free acid
Arginine
Citrulline
Sodium nitrate
Phosphatidic acid
Ursolic
acid
Curcumin
Vitamins C and E
N-3 PUFA
Resveratrol
Health and Exercise Science Research
What opportunities exist for industry-academic partnerships
in context of healthy musculoskeletal ageing?
1. Can fish oil supplementation enhance the response of MPS to
protein ingestion in active older adults? Protection against muscle
disuse?
2. Can vitamin D supplementation enhance the response of MPS to
protein ingestion in active older adults?
3. Can the anti-inflammatory and antioxidant nutrients such as
resveratrol and curcumin protect ageing muscles against
sarcopenia?
4. Is there a role for other neutraceutical compounds such as
phosphatidic acid and ursolic acid in reducing the age-related
loss of muscle mass?
Health and Exercise Science Research
26
Acknowledgements
Health and Exercise Science Research
Oliver Witard
Thanks for listening..……
………. any questions?
@OllyWitard
27
Health and Exercise Science Research
Additional slides
28
Health and Exercise Science Research
29 Report of the European working group on sarcopenia in older people
Cruz-Jentoft 2010 Age and Ageing 39: 412-423.
What criteria should be used to diagnose sarcopenia?
2. Measure grip strength
Normal ♂ ≥ 30 kg
♀ ≥ 20 kg
Low ♂ ≤ 7.25 kg/m2
♀ ≤ 5.67 kg/m2
Normal ♂ ≥ 7.25 kg/m2
♀ ≥ 5.67 kg/m2
No sarcopenia Sarcopenia
1. Measure gait speed
No sarcopenia
Older adult (> 65 years)
3. Measure muscle mass
Low ♂ ≤ 30 kg
♀ ≤ 20 kg
Sarcopenia
≤ 0.8 m/s > 0.8 m/s
Health and Exercise Science Research
30
What are prevalence estimates of sarcopenia?
1. On average, 5-13% of older adults aged 60-70 years are affected by
sarcopenia.
2. On average, 11-50% of older adults aged 80+. Briefly review best
protein nutrition practice for ageing muscles.
3. What about 40 and 50 year olds?
Health and Exercise Science Research
What is mTOR and why should we care in terms of healthy
ageing?
MYOFIBRILLAR PROTEIN SYNTHESIS
mTORC1
p70S6K1 4E-BP1
AMPK
REDD1/2
Akt MAP4K3
↓ energy status Hypoxia
EAA
(Leucine) Exercise
TSC1
TSC2
BNIP-3
Insulin
hVps34
Drummond et al 2009 J Appl Phys
Health and Exercise Science Research
What is the biological rationale for leucine fortification?
MYOFIBRILLAR PROTEIN SYNTHESIS
mTORC1
p70S6K1 4E-BP1
AMPK
REDD1/2
Akt MAP4K3
↓ energy status Hypoxia
EAA
(Leucine) Exercise
TSC1
TSC2
BNIP-3
Insulin
hVps34
Drummond et al. 2009 J Appl Phys
Health and Exercise Science Research
Fortifying a suboptimal protein dose with leucine “rescues”
a submaximal response of muscle protein synthesis
Bukhari et al. 2015 Am J Phys
• Study cohort of older women (~65
years old)
• Acute bout of single-leg resistance
exercise
• Meal-like whey protein dose vs.
leucine enriched suboptimal EAA
dose
WP L-EAA
0.00
0.04
0.08
0.12FedFasted
Muscle protein synthesis (%/h)
Health and Exercise Science Research
Muscle protein synthesis (%/h)
• Active young (~26 years) men
• Leucine (3.42 g L-leucine + ~400 mL
water)
• HMB (3.42 g free-acid form ß-hydroxyl-ß-
methylbutyrate)
• HMB (3 g calcium form ß-hydroxyl-ß-
methylbutyrate)
Leucine and HMB ingestion stimulates muscle protein
synthesis at rest in young men
Wilkinson et al. 2013 J. Phys.
Wilkinson et al. 2017 J. Phys.
Bas
al
Leuc
ine
HM
B-free
acid
HM
B-calcium
0.00
0.02
0.04
0.06
0.08
0.10 *
Health and Exercise Science Research
Myofibrillar-MPS
• Physically-active young adults
• Rex + EE + HIIT
• 25 g whey protein or 25 g whey protein + 1.5 g/ kg
BM alcohol
• Resting and post-exercise measurements of MPS
Parr et al. 2014 PlosOne
Alcohol consumption impairs the MPS response to protein
ingestion during exercise recovery
Rest PRO ALC+PRO
0.00
0.02
0.04
0.06
0.08
a
b
c
Health and Exercise Science Research
36
LBM (Kg)
Hoffman et al. 2012 J Int Soc Sp Nutr Joy et al. 2014 Nutr and Metab
Phosphatidic
acid Placebo
Pre Post Pre Post
40
50
60
70
80
LBM (Kg) Phosphatidic
acid
Placebo
Pre Post Pre Post
40
50
60
70
80*
Mixed findings from studies examining the ergogenic role
of phosphatidic acid on muscle growth
Health and Exercise Science Research
0 1 2 4-1.00
0.00
1.00
2.00
3.00
4.00
*
Focal adhesion
Kinase (FAK) activity
Week
The incorporation of EPA/DHA into the muscle phospholipid
membrane upregulates anabolic cell signaling
0 1 2 4
0.0
2.0
4.0
6.0
8.0
10.0
Week
EP
A +
DH
A (
% o
f to
tal f
att
y a
cid
s)
a
c
A
a,bb
0 1 2 4
0.0
2.0
4.0
6.0
8.0
10.0
12.0
14.0
Week
n-3
PU
FA
(%
of to
tal fa
tty
ac
ids
)
a a,b
b
c
B
McGlory et al. 2014 Prostaglandins Leukot. Essent Fatty Acids,
Basal Fed Basal Fed
0.00
0.50
1.00
1.50
2.00
2.50
*
mTORC1
phosphorylation
Pre
supplementation
Post
supplementation
Smith et al. 2011 Clinical Science
Health and Exercise Science Research
Fish oil supplementation enhances exercise training
induced strength gains in older women
Rodacki et al. 2012 Am J Clin
• Healthy older (~64 years old) women
• 90 d strength training with or without fish
oil supplementation
• 2 g/day fish oil capsules
• Pre and post measurements of muscle
mass, strength and power
Knee flexor peak torque
(Nm)
Pre Post
0
10
20
30
40Placebo
Fish oil
**
*
Health and Exercise Science Research
Mu
sc
le P
rote
in B
ala
nc
e
Time
Meal (and/or
exercise
Meal (and/or
exercise)
Meal (and/or
exercise)
Redrawn from Phillips et al. 2005 JACN
Area of B > Area of A = Decrease in muscle mass
A A A
B B
+
_
Muscle loss with ageing is underpinned by a negative
net muscle protein balance
B