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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.

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

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  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. Aerobic Capacity Defines Much Of Our Biological Existence 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

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

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

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

  7. From McCardle, Katch and Katch, 1996

  8. 1 2 3 4 Columbus Instruments four lane

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

  10. MR (Maudsely Reactive) WN (Wistar Normotensive) WKY (Wistar Kyoto) M520 (Marshall) F344 (Fischer) ACI (August x Copenhagen) BN (Brown Norway) BUF (Buffalo) Founder Population Rats Were N:NIH Stock N:NIH Stock Has Wide Genetic Heterogeneity Created by outcrossing these 8 inbred strains Strains were estimated to differ widely Originated by Carl Hansen and Karen Spuhler at the NIH in 1979. Maintained by the NIH as a resource (Carl Hansen).

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

  12. Selection Across 10 Generations 35 30 Founder 25 Population n=168 20 15 10 5 0 35 Generation 5 n=250 30 Generation 5 25 20 15 Frequency 10 5 0 25 Generation 10 n=310 20 15 10 5 0 0 500 1000 1500 2000 Meters Run at Exhaustion

  13. Response to Selection 1000 900 HCR y = 37x + 540 800 r = 0.322 n = 1385 700 p < 0.001 600 Distance Run to Exhaustion (meters) 317% 500 400 LCR 300 y = -17x + 388 r = 0.368 200 n = 1204 p < 0.001 100 1 2 3 4 5 6 7 8 9 10 11 0 Generation

  14. 40 35 30 25 20 15 10 5 0 50 Ramped Running Protocol: Time Vs Distance 45 Lactate Threshold Exhaustion Time (min) Founder Population Average Run duration = 23 min distance = 355 m speed = 21 m/min Aerobic 0 100 200 300 400 500 600 700 800 900 1000 Distance Run to Exhaustion (m)

  15. 50 Ramped Running Protocol: Time Vs Distance High 45 40 35 30 Founder Time (min) 25 20 Low 15 10 5 217 355 904 0 0 100 200 300 400 500 600 700 800 900 1000 Distance Run to Exhaustion (m)

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

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

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

  19. 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).

  20. 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].

  21. 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 T. Kurtz UCSF T. Clausen Copenhagen Mayo E. Ritman USDA L. Klevay

  22. End

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