Genetic Models of Low and High Aerobic Capacity
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Steven L. Britton and Lauren Gerard Koch Genetic Models of Low and High Aerobic Capacity Functional Genomics Laboratory Medical College of Ohio Toledo, Ohio Nature 291:381, 1981 From Alberts, et al, Molecular Biology of the Cell 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 -3.5 Billion Years Evolutionary Time Current Aerobic Capacity Aerobic Capacity Has An Ubiquitous Influence (axiomatic from our evolutionary history) Cancer Diabetes Aerobic Heart Mellitus Capacity Failure Aging Assumption Current Aerobic = Intrinsic + Adaptational Phenotype Sedentary, Response to Untrained Training Model One: Artificial Selection for Intrinsic Aerobic Endurance Treadmill Running Capacity From McCardle, Katch and Katch, 1996 1 2 3 4 30 RAT ENDURANCE RUN TO EXHAUSTION Speed-Ramped Protocol Start = 10 m/min Increased 1 m every 2 min Speed (m/min) 25 20 “Average” rat 15 exhausted at 10 23 min 5 -5 0 5 10 15 20 25 Duration of Run (min) treadmill shock grid 15 degrees 30 35 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 • • • • 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 Running Capacity 900 800 Thirteen mating pairs that started the high selected line f Distance Run (meters) 700 600 500 400 Distance Thirteen mating pairs that started the low selected line 88 Females 541 m 300 205 m 80 Males 200 100 633 m 167 m 0 Founder Population Ranked from Low to High Capacity Frequency Selection Across 10 Generations 35 30 25 20 15 10 5 0 35 30 25 20 15 10 5 0 Founder Population n=168 Generation 5 Generation 5 n=250 25 20 Generation 10 15 n=310 10 5 0 0 500 1000 1500 Meters Run at Exhaustion 2000 Response to Selection Distance Run to Exhaustion (meters) 1000 900 HCR y = 37x + 540 r = 0.322 n = 1385 p < 0.001 800 700 600 317% 500 400 LCR y = -17x + 388 r = 0.368 n = 1204 p < 0.001 300 200 100 0 1 2 3 4 5 6 Generation 7 8 9 10 11 50 Ramped Running Protocol: Time Vs Distance 45 40 Time (min) 35 Lactate Threshold 30 Exhaustion 25 Founder Population Average Run 20 15 duration = 23 min Aerobic 10 distance = 355 m 5 speed = 21 m/min 0 0 100 200 300 400 500 600 700 Distance Run to Exhaustion (m) 800 900 1000 50 Ramped Running Protocol: Time Vs Distance High 45 40 Time (min) 35 30 Founder 25 20 Low 15 10 5 217 355 904 0 0 100 200 300 400 500 600 700 Distance Run to Exhaustion (m) 800 900 1000 Low Capacity Gained and High Capacity Lost Weight 350 Low y = 4.2x + 279 R = 0.90 Male Body Weight (grams) 300 250 High y = -1.1x + 266 R = 0.33 200 Low y = 3.3x + 178 R = 0.93 Female High y = -1.1x + 179 R = 0.79 150 0 1 2 3 4 5 Generation 6 7 8 9 10 11 12 26 Low Parents IIIIIIIIIIIIIIIIIIIIIIIII IIIIIIII IIIIIIIIIIII IIIIIIIIIIIIIIIIIIIIII IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII 168 Founders 26 High Parents IIIIIIIIIIIIIIIIIIIIIIIII Thirteen LCR Families 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 G2 IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII G3 IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII G4 IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII G5 IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII G6 IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII G7 IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII G8 IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII G9 IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII G10 IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII G11 IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII The entire parental DNA (II) architecture is archived 26 Low Parents IIIIIIIIIIIIIIIIIIIIIIIII IIIIIIII IIIIIIIIIIII IIIIIIIIIIIIIIIIIIIIII IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII 168 Founders 26 High Parents IIIIIIIIIIIIIIIIIIIIIIIII Thirteen HCR Families 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 G2 IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII G3 IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII G4 IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII G5 IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII G6 IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII G7 IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII G8 IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII G9 IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII G10 IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII G11 IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII IIIIIIII 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). 2.5 Heat Shock Protein 70i 2 Left Ventricle Sedentary Rats 1.5 1 0.5 0 LCR HCR 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 UCSD U Kansas Laval (Can.) Yale Bouchard Wagner Gonzales St. Amand U. Norway UCSF Neuffer U. Wisloff T. Kurtz Copenhagen T. Clausen Mayo USDA E. Ritman L. Klevay End
