Steven L. Britton and Lauren Gerard Koch Functional Genomics Laboratory Medical College of Ohio

Steven L. Britton

and

Lauren Gerard Koch

Functional Genomics Laboratory

Medical College of Ohio

Toledo, Ohio

Genetic Models of Low and High

Aerobic Capacity

Nature 291:381, 1981

From Alberts, et al, Molecular Biology of the Cell

Photosynthesis

Created Atmospheric Oxygen(increased redox potential more free energy)

Created a Permissive Environment for Evolution of Complex Aerobic Pathways

Current Aerobic Capacity

-3.5 Billion Years

Evolutionary Time

Aerobic Capacity Defines Much Of Our Biological Existence

Aerobic

Capacity

Cancer

Diabetes

Mellitus

Heart

Failure

Aging

Aerobic Capacity Has An Ubiquitous Influence

(axiomatic from our evolutionary history)

Current

Aerobic = Intrinsic + Adaptational

Phenotype

Sedentary,

Untrained

Response to

Training

Assumption

Model One:

Artificial Selection for

Intrinsic Aerobic Endurance

Treadmill Running Capacity

From McCardle, Katch and Katch, 1996

Columbus Instruments four lane

1

2

3

4

treadmill

shock grid 15 degrees

RAT ENDURANCE RUN TO EXHAUSTION

5

10

15

20

25

30

-5 0 5 10 15 20 25 30 35Duration of Run (min)

Sp

ee

d (

m/m

in)

Speed-Ramped ProtocolStart = 10 m/minIncreased 1 m every 2 min

“Average” rat

exhausted at

23 min

N:NIH Stock Has Wide Genetic Heterogeneity Created by outcrossing these 8 inbred strains

Strains were estimated to differ widely

• MR (Maudsely Reactive)

• WN (Wistar Normotensive)

• WKY (Wistar Kyoto)

• M520 (Marshall)

• F344 (Fischer)

• ACI (August x Copenhagen)

• BN (Brown Norway)

• BUF (Buffalo)

Originated by Carl Hansen and Karen Spuhler at the NIH in 1979. Maintained by the NIH as a resource (Carl Hansen).

Founder Population Rats Were N:NIH Stock

0

100

200

300

400

500

600

700

800

900

Dis

tan

ce

Ru

n (

me

ters

)

88 Females

80 Males

Thirteen mating pairs that started the high selected line

Thirteen mating pairs that started the low selected line

Founder Population Ranked from Low to High Capacity

Founder Population Running Capacity

205 m

167 m

633 m

541 m

f

Distance

0

5

10

15

20

25

0 500 1000 1500 2000

FounderPopulation

n=168

05

101520253035

Generation 5

05

101520253035

Frequency

Selection Across 10 Generations

Meters Run at Exhaustion

Generation 5

n=250

Generation 10

n=310

100

200

300

400

500

600

700

800

900

1000

0 1 2 3 4 5 6 7 8 9 10 11

Generation

Dis

tan

ce

Ru

n t

o E

xh

au

sti

on

(m

ete

rs)

HCRy = 37x + 540r = 0.322n = 1385p < 0.001

LCRy = -17x + 388r = 0.368n = 1204p < 0.001

317%

Response to Selection

45

50

0 100 200 300 400 500 600 700 800 900 1000

Distance Run to Exhaustion (m)

Tim

e (m

in)

Ramped Running Protocol:Time Vs Distance

0

5

10

15

20

25

30

35

40

Aerobic

Lactate Threshold Exhaustion

Founder Population Average Run

duration = 23 min

distance = 355 m

speed = 21 m/min

45

50

0 100 200 300 400 500 600 700 800 900 1000

Distance Run to Exhaustion (m)

Tim

e (

min

)

Ramped Running Protocol: Time Vs Distance

0

5

10

15

20

25

30

35

40

Founder

Low

High

217 355 904

Low y = 4.2x + 279R = 0.90

Highy = -1.1x + 266R = 0.33

Lowy = 3.3x + 178R = 0.93

Highy = -1.1x + 179R = 0.79

150

200

250

300

350

0 1 2 3 4 5 6 7 8 9 10 11 12

Generation

Bo

dy W

eig

ht

(gra

ms)

Male

Female

Low Capacity Gained and High Capacity Lost Weight)

1 2 3 4 5 6 7 8 9 10 11 12 13

G1 IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII











IIIIIIIIIIIIIIIIIIIIIIIII

IIIIIIIIIIIIIIIIIIII

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII IIIIIIIIIIIIIIIIIIIIIIIII

168 Founders

26 Low Parents 26 High Parents

Thirteen LCR Families

The entire parental DNA (II) architecture is archived

1 2 3 4 5 6 7 8 9 10 11 12 13












IIIIIIIIIIIIIIIIIIIIIIIII

IIIIIIIIIIIIIIIIIIII

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII IIIIIIIIIIIIIIIIIIIIIIIII

168 Founders

26 Low Parents 26 High Parents

Thirteen HCR Families

The entire parental DNA (II) architecture is archived

Likely Determinant Phenotype

HCR are higher than LCR for:

1. Isolated Cardiac Output (John Barbato).

2. Cardiac left ventricular myosin ATPase activity (John Barbato).

3. Cardiac left ventricular Na+/K+ ATPase (Joseph Shapiro).

4. Stress Proteins (HSP 70 inducible) in heart and skeletal muscle (Ed Sanchez

and Todd Brickman).

0

0.5

1

1.5

2

2.5

LCR HCR

Hea

t S

hoc

k P

rote

in 7

0iLeft VentricleSedentary Rats

Other Selectivley-Bred Models in Development

1. Adaptational response to endurance training

2. Sensorimotor capacity (coordination)

Long-term, we want to make these models available for others to study.

[The NIH has provided resources to make the

Intrinsic Aerobic Rats available for small-scale studies].

We have collaborations with 10 institutions, but no formal,

systematic plans for studying these models.

Pennington Bouchard

UCSD Wagner

U Kansas Gonzales

Laval (Can.) St. Amand

Yale Neuffer

U. Norway U. Wisloff

UCSF T. Kurtz

Copenhagen T. Clausen

Mayo E. Ritman

USDA L. Klevay

End

Documents

Steven L. Britton and Lauren Gerard Koch Functional Genomics Laboratory Medical College of Ohio