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

treadmill shock grid 15 degrees RAT ENDURANCE RUN TO EXHAUSTION “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 Maintained by the NIH as a resource (Carl Hansen). Founder Population Rats Were N:NIH Stock

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

Founder Population n= Generation Frequency Selection Across 10 Generations Meters Run at Exhaustion Generation 5 n=250 Generation 10 n=310

Generation Distance Run to Exhaustion (meters) HCR y = 37x r = n = 1385 p < LCR y = -17x r = n = 1204 p < % Response to Selection

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

Distance Run to Exhaustion (m) Time (min) Ramped Running Protocol: Time Vs Distance Founder Low High

Male Female Low Capacity Gained and High Capacity Lost Weight )

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

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

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).

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 UCSDWagner U KansasGonzales Laval (Can.)St. Amand Yale Neuffer U. NorwayU. Wisloff UCSF T. Kurtz Copenhagen T. Clausen MayoE. Ritman USDAL. Klevay

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