1. Steven L. Britton and Lauren Gerard Koch Functional Genomics Laboratory Medical College of Ohio Toledo, Ohio Genetic Models of Low and High Aerobic Capacity

2. Nature 291:381, 1981 From Alberts, et al, Molecular Biology of the Cell

3. 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

4. Aerobic Capacity Cancer Diabetes Mellitus Heart Failure Aging Aerobic Capacity Has An Ubiquitous Influence (axiomatic from our evolutionary history)

5. Current Aerobic = Intrinsic + Adaptational Phenotype Sedentary, Untrained Response to Training Assumption

6. Model One: Artificial Selection for Intrinsic Aerobic Endurance Treadmill Running Capacity

7. From McCardle, Katch and Katch, 1996

9. Columbus Instruments four lane 1 2 3 4

10. treadmill shock grid 15 degrees RAT ENDURANCE RUN TO EXHAUSTION “Average” rat exhausted at 23 min

11. 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

12. Founder Population Running Capacity 205 m 167 m 633 m 541 m f Distance

13. 0 5 10 15 20 25 0500100015002000 Founder Population n=168 0 5 10 15 20 25 30 35 Generation 5 0 5 10 15 20 25 30 35 Frequency Selection Across 10 Generations Meters Run at Exhaustion Generation 5 n=250 Generation 10 n=310

14. 100 200 300 400 500 600 700 800 900 1000 0 1234567891011 Generation Distance Run to Exhaustion (meters) HCR y = 37x + 540 r = 0.322 n = 1385 p < 0.001 LCR y = -17x + 388 r = 0.368 n = 1204 p < 0.001 317% Response to Selection

15. 45 50 01002003004005006007008009001000 Distance Run to Exhaustion (m) Time (min) Ramped Running Protocol: Time Vs Distance Aerobic Lactate Threshold Exhaustion Founder Population Average Run duration = 23 min distance = 355 m speed = 21 m/min

16. 45 50 01002003004005006007008009001000 Distance Run to Exhaustion (m) Time (min) Ramped Running Protocol: Time Vs Distance 0 5 10 15 20 25 30 35 40 Founder Low High 217355 904

17. Male Female Low Capacity Gained and High Capacity Lost Weight )

18. IIIIIIIIIIIIIIIIIIIIIIIII IIIIIIII IIIIIIIIIIII IIIIIIIIIIIIIIIIIIIIII IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII IIIIIIIIIIIIIIIIIIIIIIIII 168 Founders 26 Low Parents26 High Parents Thirteen LCR Families The entire parental DNA (II) architecture is archived

19. IIIIIIIIIIIIIIIIIIIIIIIII IIIIIIII IIIIIIIIIIII IIIIIIIIIIIIIIIIIIIIII IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII IIIIIIIIIIIIIIIIIIIIIIIII 168 Founders 26 Low Parents26 High Parents Thirteen HCR Families The entire parental DNA (II) architecture is archived

20. 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).

22. 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].

23. We have collaborations with 10 institutions, but no formal, systematic plans for studying these models. Pennington Bouchard UCSDWagner U KansasGonzales Laval (Can.)St. Amand Yale Neuffer U. NorwayU. Wisloff UCSF T. Kurtz Copenhagen T. Clausen MayoE. Ritman USDAL. Klevay

24. End