Genes, Environments and Human Development, Health and Genes, Environments and Human Development, Health and DiseaseDisease

ExerciseExercise

Dan M. Cooper MD

Main PointsMain Points

1.1.Exercise is DANGEROUSExercise is DANGEROUS

2.2.Physical activity alters growth and Physical activity alters growth and developmentdevelopment

3.3.Physical activity influences health and Physical activity influences health and disease disease

4.4.Brief bouts of exercise alter leukocyte Brief bouts of exercise alter leukocyte gene expressiongene expression

5.5.The search for “fitness” genes is The search for “fitness” genes is ongoing and complex.ongoing and complex.

1.1. Exercise is DANGEROUSExercise is DANGEROUS

Exercise-induced Exercise-induced anaphylaxisanaphylaxis

“Be honest—how much are you exercising?”

2.2.Physical activity alters growth and Physical activity alters growth and developmentdevelopment

Exercise Growth Hormone

IGF-I

Stimulates local tissues (?IGF-I) directly

Target Tissues

? GH binding

proteins

? IGF binding proteins

? BP Proteolysis

? mechanisms

Change in key growth Change in key growth and stress mediators and stress mediators in 51 healthy, growing, in 51 healthy, growing, premature babies over premature babies over a 4-6 week period in a 4-6 week period in the UCI NICU the UCI NICU

Physical Physical InactivityInactivity

++Diet high in Diet high in

fat and fat and caloriescalories

++Maturational Maturational

StatusStatus++

EnvironmentEnvironmental Factorsal Factors

++Genetic Genetic FactorsFactors

In otherwise healthy children...In otherwise healthy children...

= obesity, metabolic syndrome, asthma, = obesity, metabolic syndrome, asthma, adult cardiovascular disease, canceradult cardiovascular disease, cancer

3. Physical activity influences health and disease3. Physical activity influences health and disease

Physiological Physiological constraintsconstraints

++Abnormal Abnormal

inflammatorinflammatory responsesy responses

++Maturational Maturational

StatusStatus++

EnvironmentEnvironmental Factorsal Factors

++Genetic Genetic FactorsFactors

In children with chronic disease and In children with chronic disease and disability…disability…

= narrow range of optimal exercise= narrow range of optimal exercise

PHYSICAL ACTIVITYPHYSICAL ACTIVITY

Growth Growth MechanismsMechanisms

Stress/Inflammatory Stress/Inflammatory MechanismsMechanisms

Innate and Adaptive Innate and Adaptive ImmunityImmunity•Inflammatory cytokinesInflammatory cytokines•PBMCsPBMCs

Anabolic FactorsAnabolic Factors•Pituitary GHPituitary GH•IGF-I systemIGF-I system

Health Health EffectsEffects

Growth Growth EffectsEffects

““Critical Periods”Critical Periods” EnvironmentEnvironmentGenGenee

Physical Activity, Health, and Growth in Children—Physical Activity, Health, and Growth in Children—Potential MechanismsPotential Mechanisms

??

?? ??

4. Brief bouts of exercise alter 4. Brief bouts of exercise alter leukocyte gene expressionleukocyte gene expression

ExerciseExercise

Possible Mechanisms of Exercise Modulation of Possible Mechanisms of Exercise Modulation of WBC Gene ExpressionWBC Gene Expression

DIRECT EFFECTS:DIRECT EFFECTS:Heat, Hypoxia, Heat, Hypoxia, Acidosis, Acidosis, Catecholamines,IL-6Catecholamines,IL-6

BaselineBaseline

Global SignalGlobal Signal

INDIRECT EFFECTS:INDIRECT EFFECTS:Recruitment of leukocytes Recruitment of leukocytes from depots (lung, from depots (lung, demargination, lymph demargination, lymph tissue, bone marrow)tissue, bone marrow)

Post ExercisePost Exercise

Global SignalGlobal Signal

Leukocytes expressing different genes

Impact of Brief Exercise on Representative PBMC Gene Impact of Brief Exercise on Representative PBMC Gene Expression in Children: A Comparison of RT-PCR vs AffyU133Expression in Children: A Comparison of RT-PCR vs AffyU133

0 1 2 3 4 50.0

0.5

1.0

1.5

2.0

2.5

AffyU133 (peak/base)

RT

-PC

R (

pea

k/b

ase)

HSPA1BHSPA1B

HSPA8HSPA8

CTSWCTSW

GRZBGRZB

CASP6CASP6

TBX21TBX21

R=0.90R=0.90

EnvironmenEnvironmentt

GenotypeGenotype

PhenotypPhenotypee

Previous ApproachPrevious Approach

EnvironmenEnvironmentt

GenotypeGenotype

Emerging Emerging ApproachApproach

PhysiologicPhysiological al

ChallengeChallenge

Regulatory Regulatory ResponseResponse

IntermediatIntermediate e

PhysiologicaPhysiologicall

PatternsPatterns

Thanks for your attention!Thanks for your attention!

We would like to acknowledge the NIH support for this work:We would like to acknowledge the NIH support for this work:

UCI GCRC--MO1 RR00827, RO1 NHLBI 080947, PO1 NICHD UCI GCRC--MO1 RR00827, RO1 NHLBI 080947, PO1 NICHD 048721 048721