Download Physical inactivity as a mediator of chronic diseases

Physical inactivity has been established
as the cause of many chronic diseases
Coronary artery disease
• “Physical inactivity — An inactive
lifestyle is a risk factor for coronary
heart disease.” American Heart Association
• Inactivity increases the risk of coronary
artery disease by 45% Katzmarzyk &
Janssen. Can J Appl Physiol 29:90, 2004
Stroke
• “Physical inactivity and obesity —
Being inactive, obese or both can
increase your risk of high blood
pressure and stroke.” American Stroke
Association
• Inactivity increases the risk of stroke
by 60% Katzmarzyk & Janssen. Can J Appl
Physiol 29:90, 2004
Hypertension
• “Being inactive, obese or both can
increase your risk of high blood
pressure.” American Heart Association
• Inactivity increases the risk of
hypertension by 30% Katzmarzyk & Janssen.
Can J Appl Physiol 29:90, 2004
Colon cancer
• “Physical inactivity: If you are not
physically active, you have a greater
chance of developing colorectal
cancer.” American Cancer Society
• Inactivity increases the risk of colon
cancer by 41% Katzmarzyk & Janssen. Can J
Appl Physiol 29:90, 2004
Breast Cancer
• “Physical activity: Evidence is growing
that physical activity in the form of
exercise reduces breast cancer risk.”
American Cancer Society
• Inactivity increases the risk of breast
cancer by 31% Katzmarzyk & Janssen. Can J
Appl Physiol 29:90, 2004
Type 2 diabetes
• “Diabetes Prevention Program study
conclusively showed that people with
pre-diabetes can prevent the
development of type 2 diabetes by
making changes in their diet and
increasing their level of physical
activity.” American Diabetes Association
• Inactivity increases the risk of type 2
diabetes by 50% Katzmarzyk & Janssen. Can
J Appl Physiol 29:90, 2004
Osteoporosis
• “Getting little or no weight-bearing
exercise, increases your chances of
developing osteoporosis.” National
Osteoporosis Foundation
• Inactivity increases the risk of
osteoporosis by 59% Katzmarzyk & Janssen.
Can J Appl Physiol 29:90, 2004
Physical Activity Reduces the Risk on
Many Chronic Diseases
• Physical inactivity increases risk of:
– Coronary artery disease
(by 45%)
– Stroke
(by 60%)
– Hypertension
(by 30%)
– Colon cancer
(by 41%)
– Breast cancer
(by 31%)
– Type 2 diabetes
(by 50%)
– Osteoporosis
(by 59%)
Katzmarzyk & Janssen. Can J Appl Physiol 29:90, 2004
Additional conditions whose prevalence
is increased by physical inactivity
•
•
•
•
•
•
•
•
•
•
•
Arthritis pain
Arrhythmias
Congestive heart failure
Depression
Digestive problems
Gallstone disease
High blood triglyceride
High blood cholesterol
Hypertension
Impotence
Less cognitive function
Additional conditions whose prevalence
is increased by physical inactivity
•
•
•
•
•
•
•
•
•
•
Low blood HDL
Lower quality of life
Menopausal symptoms
Obesity
Peripheral vascular disease
Physical frailty
Premature mortality
Prostate cancer
Respiratory problems
Sleep apnea
Physical inactivity increases the progression of
9 disabilities resulting from conditions such as:
•
•
•
•
•
•
•
•
•
Chemotherapy
Chronic back pain
Debilitating illnesses
Disease cachexia
Falls resulting in broken hips
Physical frailty
Spinal cord injury
Stroke
Vertabral/femoral fractures
Major site of chronic disease
• Blood vessels
–
–
–
–
Atherosclerosis
Hypertension
Peripheral vascular disease
Stroke
• Bone
– Loss of immunity
– Osteoporesis
• Brain
– Alzheimer’s Disease
– Dementia
– Depression
• Cancer
– Breast
– Colon
Major site of chronic disease
• Cartilage
– Atrophy
• Heart
– Congestive Heart Failure
• Liver
– Non-alcoholic fatty liver disease
• Penis
– Impotence
• Tendon
– Atrophy
• Multiple sites
– Obesity
– Type 2 Diabetes
– Sarcopenia
Summary
Physical inactivity produces chronic
diseases
What is the reason/mechanism?
Is there a reason that the body
evolved to react so negatively to
physical inactivity?
Speculation
Physically trained condition served as a
metabolic bank during evolution by
having the bank reserves to draw on in
infection and starvation…
…That is the need for calories
supersedes needs for high physical
capacity in infection and starvation
Is there a reason that the body
evolved to react so negatively to
physical inactivity?
Speculation
Physically trained condition served as a
metabolic bank during evolution by
having the bank reserves to draw on in
infection and starvation…
…
Allows greater insight
to make testable hypotheses
Is there a reason that the body
evolved to react so negatively to
physical inactivity?
Speculation
Physically trained condition served as a
metabolic bank during evolution by
having the bank reserves to draw on in
infection and starvation…
…also implies that skeletal muscle
must have selected plasticity to regain
banked deposits of lost amino acids
Why does physical inactivity, alone,
draw on the metabolic bank?
• Rapid adaptation to survive in new
environment by
• Supplying amino acids to liver
for gluconeogenesis
• Switching between trained
phenotypes (aerobic to strength
Physical inactivity models of chronic disease
Animal (Booth)
↕
Human (Pederson)
Wks of natural daily running denied after wks of
running decreases muscle insulin sensitivity
http://www.minimitter.com/Products/Nalgene/RunningWheels.html
Daily running distances of Fischer
344 x Brown Norway rats over 6 wks
Stop native
voluntary
running
Laye JAP 2006
What are initial metabolic changes
leading to increased risk factors
Omental
fat pad
mass
(g)
Omental
weight
(g)
Rat – Omental fat pad mass increases
48% with reduced physical activity
0.2
48%
*
*
0.1
0.0
WL5
5
WL29
29
WL53
53
SED5
SED
Hours inactivity
Kump and Booth, J Physiol
Rat – the reduction in caloric intake does not
prevent an increase in adipose tissue mass
due to decreased physical activity
0
2
7
Days
Laye. JAP 102:1341 , 2007
Rat Body Composition Significantly Changes
with 7 Days of Reduced Physical Activity
8
*
Bo dy Fat %
7
6
5
4
3
Le an Bo dy Mas s (g )
230
+
220
++
210
200
190
180
WL5
WL173
SED
1 We e k Out
Week
Day o f S1ac
rificOut
e
Day of Sacrifice
Laye. JAP 102:1341 , 2007
Human – healthy young men not in exercise programs,
2-wk reduction in daily steps from 10,501 to 1344
Pedersen
Olsen JAMA 299:1261, 2008
Intra-abdominal fat (grams)
Humans – intra-abdominal fat increased 7%
after two wks of reduced stepping
Pedersen
850
Same subjects – paired t test
*
800
750
700
650
600
1
Pre
After 22 wks
reduced steps
Olsen JAMA 299:1261, 2008
Humans – total fat mass does not change with
reduced steps from 10,000 to 1500 in 2 wks
Total Fat Mass
13
12
11
10
9
8
7
Before
After
6
Olsen JAMA 299:1261, 2008
Humans – total muscle mass decreased 2% with
reduced steps from 10,501 to 1344 in 2 wks
Total Muscle Mass
55
54,8
54,6
54,4
54,2
54
53,8
53,6
53,4
53,2
53
1.2 kg
Before
Olsen JAMA 299:1261, 2008
After
p < 0.05
Rat Body Composition Significantly Changes
with 7 Days of Reduced Physical Activity
8
*
Bo dy Fat %
7
6
5
4
3
Le an Bo dy Mas s (g )
230
+
220
++
210
200
190
180
WL5
WL173
SED
1 We e k Out
Week
Day o f S1ac
rificOut
e
Day of Sacrifice
Laye and Booth
enhances decrease in protein synthesis,
Physical inactivity
in
increase in protein degradation, and loss of tissue mass
Physical
inactivity
in
Glucose
Synthesis
Liver
Protein
quantity
Amino
acids
Caloric deficit or
infection (cytokine
malnutrition)
Degradation
Physical
inactivity
in
(µmol/ml intracellular
Glucose
into muscle
space/min)
Rats – cessation of voluntary running decreases
submaximal insulin-stimulated 2-deoxyglucose
uptake into the epitrochlearis muscle
2 days * p<0.05 vs. WL5
1.4
1.2
*
1.0
*
0.8
0.6
0.4
0.2
0.0
WL29
SED5
5
29 WL53
53 SED
Hours inactivity
WL5
Kump and Booth. J Physiol 562:829, 2005
Humans – decreased glucose infusion in
euglycemic insulin clamp (GIR) after 2 wks of
reduced steps from 10,000 to 1500/day
*
1400
Before
1200
mg/kg/mi n
1000
800
600
After
400
200
0
0
50
100
150
200
250
min
Pedersen
Olsen JAMA 299:1261, 2008* p < 0.05
300
Akt Ser473
phosphorylation/total
Akt (relative band density)
Rat - decreased Akt-Ser473 phosphorylation
2 days after ceasing 21 days
of voluntary wheel running
2.0
1.5
1.0
**
**
53
WL53
SED
SED
0.5
0.0
5
WL5
29
WL29
Hours inactivity
Kump J Physiol 562:829, 2005
Human – 2 wks of lowing steps from 10,000/d (Pre) to 1500/d
(Post) reduces muscle Akt tyrosine phosphorylation
P
R
E
P
O
S
T
Clamp Time
Olsen JAMA 299:1261, 2008
Local physical inactivity
shuts down
in
insulin-stimulated glucose uptake in quiescent muscles to
Physical
inactivity
Lose muscle
insulin
sensitivity
Conserve blood glucose
Convert glucose to fat
Replenish liver glycogen
Skeletal
muscle
Gain muscle
insulin sensitivity
Physical
activity
Supply glucose to contracting muscle
Humans – no suppression of liver glucose production (Ra), but
reduced peripheral glucose uptake (Rd) after reduced steps.
*
11000
µmol/kg
9000
Pre
7000
Post
5000
pre
post
3000
1000
Ra
Pedersen
Rd
Olsen JAMA 299:1261, 2008
(7 days) shifts fatty acid oxidation
Rat – physical inactivity
in
from formally contracting skeletal muscle to liver
Physical
inactivity
in
Muscle fatty acid oxidation
Liver fatty acid oxidation
Physical
inactivity
in
Laye
Rat liver
Saturated fatty acid oxidation increases in first 7
days after cessation of daily running
Speculation – protecting against overflow of fatty
acids not oxidized by inactive skeletal muscle
+ Voluntary Wheel Running
+ Food Intake
Summary
No Change in Cell Size
No Change in Macrophage Infiltration
No Change in GLUT4 Protein
Skeletal Muscle
Skeletal Muscle
+ Voluntary Wheel Running
Dogma for medicine is:
Healthiest group is control
Sickest group is treatment group
Dogma for medicine is:
Healthiest group is control
Sickest group is treatment group
Dogma for exercise is:
Healthiest group is trained
Sickest group is sedentary treatment group
Dogma for medicine is:
Healthiest group is control
Sickest group is treatment group
Dogma for exercise is:
Healthiest group is trained
Sickest group is sedentary treatment group
Dogma for exercise medicine is:
Healthiest group is trained
Sickest group is sedentary treatment group
Environment in which genome evolved forms
genetic control group (normal phenotype for genes)
C
O
N
T
I
N
U
M
Exercise
Train
Activity state
Elite athlete
Detraining
Physically active
Control / normal
Physically
active
Physically
inactive
Sedentary
Rehabilitation
Exercise
Debilitation
Bed rest
Booth Med Sci Sports Exercise 38:405, 200
Exercise –
Are you studying mechanisms for compensation
(treatment)?
Inactivity –
Are you studying mechanisms for cause
(prevention)?
Are mechanisms of exercise
an exact reversal of mechanisms of inactivity?
Are mechanisms of exercise
an exact reversal of mechanisms of inactivity?
Are all molecules the same,
and if the same reversible for
•Lipolysis = lipogenesis
•Glycolysis = glycogen synthesis
•Protein degradation = protein synthesis
Why would the body have been constructed to lose
functional capacity when it is not used?
Why would the body have been constructed to lose
functional capacity when it is not used?
What is its functional purpose?
Why would the body have been constructed to lose
functional capacity when it is not used?
What is its functional purpose?
How does it help survival?
Why would the body have been constructed to lose
functional capacity when it is not used?
What is its functional purpose?
How does it help survival?
Show stoppers for survival until gene pool passed to next
generation all invoke similar metabolic tools with cell
context differences
1
65%
1
Parents with diabetes
Parents without diabetes
0.8
0.8
Risk of type 2 diabetes
100%
0.6
0.6
0.4
0.4
Frank Hu
2nd
lowest
middle
Lowest
Most
Lowest
active
Parental history of diabetes present
Highest
Most
inactive
Highest
Lowest
Most active
2nd
lowest
middle
0
2nd
highest
0
Highest
Most inactive
0.2
0.2
2nd
highest
Relative risk of type 2 diabetes
Inactivity increases risk of type 2 diabetes in siblings
Parental history of diabetes absent
Quartile of physical INactivity
Quantiles of physical inactivity
Hu et al., JAMA
282:1433, 1999
Predisposing geneenvironmental interaction
• Individualized (personalized) medicine
– Is biological regulation too complex?
• Understand genetic make-up?
• Understand integration of organ systems
• Understand predisposing genes to polygenic
complex diseases?
• Understand exercise genes?
–Type (aerobic, strength, neural)
–Dosage
»Varying thresholds for each gene?
Predisposing geneenvironmental interaction
• Individualized (personalized) medicine
– Exercise target’s
• Genetic weakness or genetic strength?
• Activity-responsive genes or
predisposing disease-responsive
genes?
• Go after physical inactivity genes or
exercise genes?
Predisposing geneenvironmental interaction
• Individualized (personalized) medicine
– Art and science
• Athletic coaching is more art than medicine
• Medicine is more science than art as
compared to athletic coaching
• Does personalized medicine = personalized
coaching?
Is the goal of individualized medicine too complex?
¾Is this the only way that we can justify funding?
¾Is not the curiosity to understand how the body
functions normally in physically activity individuals
and abnormally in sedentary individuals enough to
justify funding?
¾Perform exercise research to find molecular links
to loss of health
¾Seat belts
¾Tobacco
¾Asbestos
“However, the best opportunity to reduce
risk in genetically susceptible people for
the foreseeable future will not be to reengineer their genes, but to modify their
environment.”
Francis Collins,
Director of the National Human Genome
Research Institute
Science 316: 695, 2007
“However, the best opportunity to reduce
risk in genetically susceptible people for
the foreseeable future will not be to reengineer their genes, but to modify their
environment.
We need to understand how genetic
factors and environmental exposures
interact in individuals to alter normal
biological function and to affect the risk of
disease development.”
Francis Collins,
Director of the National Human Genome
Research Institute
Science 316: 695, 2007
Thanks to
Matt Laye