artificial selection for low and high endurance exercise capacity in rats steven l. britton lauren...
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Initial idea: use artificial selection to create a low and high form for disease risks. Make contrasting models. But what trait would tell us the most about disease? I went searching……….and made guides (~1986). The model must: 1) emulate an important clinical phenotype(s) 2) be polygenic 3) respond to positive and negative health environments 4) be explained by fundamental scientific principles. Wanted the approach to be explanatory and predictive.TRANSCRIPT
Artificial selection for low and high endurance exercise capacity in rats
Steven L. Britton
Lauren Gerard Koch
University of Michigan
John P. RappStudied the genetics of Dahl
salt sensitive rats.
Starting in 1982 I was influenced by the quantitative geneticist John Rapp.
The Pioneer of Mammalian Genomics.
He stimulated me to think about animal models of complex diseases.
I studied models but could not grasp the logic.
They seemed too simplistic.Streptozotocin = diabetes?
Coronary occlusion = heart failure?Knock in/knock out?
Mutagenetics?
None captured the polygenic condition of complex diseases or followed from a hypothesis
Initial idea: use artificial selection to create a low and high form for disease risks. Make contrasting models.
But what trait would tell us the most about disease?
I went searching……….and made guides (~1986).
The model must:
1) emulate an important clinical phenotype(s) 2) be polygenic 3) respond to positive and negative health environments4) be explained by fundamental scientific principles.
Wanted the approach to be explanatory and predictive.
Energy Metabolism
Evolution +Disease
An idea emerged in ~1988I envisioned a connection between disease and evolution that
might have mechanistic value
ClinicalAssociation
Theoretical base
Clinical Association: In the 1980s
A literature emerged demonstrating a strong statistical linkage between a wide range of disease risks and low capacity for energy transfer.
On this basis I formulated the:
Energy transfer hypothesis
“Variation in capacity for energy transfer is a central mechanistic determinant of the divide between disease and health.”
[the wide ranging influence of exercise was perplexing: diabetes→heart failure→cancer→depression]
1992: I formulated that 2-way artificial selection for low and high exercise capacity would test the energy transfer hypothesis.
That is, would disease risks segregate with artificial selection for low capacity for energy transfer?
If true, it would also yield mechanism-based contrasting models for study.
This was the predictive type of approach I sought.
LOW HIGH
High Disease
Risk
Low Disease
Risk
FounderPopulation
1996capacity
n
low high
capacitylow high
capacitylow high
capacitylow high
Generation 36
2015
Energy Metabolism
Evolution +Disease
An idea emerged in ~1988I envisioned a connection between disease and evolution that
might have mechanistic value
ClinicalAssociation
Theoretical base
We thought it weak to move forward based only upon clinical association
We sought a principle-based explanation for the Energy Transfer Hypothesis.
In a very non-linear path we connected ideas from:
Evolution
Energy Metabolism
Earth’s oxygen history
Two messages in this paper: 1. Life evolves along the transfer of energy.2. More complexity equates with more energy transfer. -You don’t get something for nothing
-This paper made the obvious perfectly clear
Hans KrebsJack Baldwin
Directed us towards using evolution and thermodynamics.
The evolution of metabolic cyclesJack E. Baldwin & Hans KrebsNature 1981
Biochemical Pathways
Krebs Cycle
Energy transfer capacity evolved simultaneously with all other features.
From Alberts, et al, Molecular Biology of the Cell
Pyruvate
Acetyl CoA
Glucose
Cholesterol
THE RELATIVE ELECTRONEGATIVITY OF ATOMSLINUS PAULING
Journal of the American Chemical SocietyVolume 54, p. 3570-3582, 1932
Pauling scale: 0.7 lowest 3.98 = highest
Start with the obvious
Oxygen is special in the universe for energy transfer
Operates at the high end of the energy spectrum
Ranks #2 in electronegativity amongst all elements
photosynthesis: electrons to
carbon
respiration: electrons to
oxygen
Energy transfer is basically an electron shuttle between oxygen and carbon.
Pauling Electronegativity Scale (0.9 to 4.1)
As a heuristic, we synthesized bio-complexity and earth’s oxygen history to a one page picture.
1. The rise of oxygen over the past 205 million years and the evolution of large placental mammals. Paul Falkowski, Science (2005).2. The oxygenation of the atmosphere and oceans. Heinrich Holland, Philos Trans R Soc Lond B Biol Sci (2006).3. Why O2 is required by complex life on habitable planets and the concept of planetary "oxygenation time?" David Catling et al, Astrobiology (2005).4. A molecular time scale of eukaryote evolution and the rise of complex multicellular life.Blair Hedges, et al, BMC Evolutionary Biology (2004)
Koch & Britton, J. Physiology, 2008 Adobe Acrobat
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0
50
100
150
200
250
300
012345Billions of years ago (Ga)
Atmospheric oxygen (m
m Hg)
Number of cell types
4.6 Earth formation
3.7 First living cells
3.3 Anoxygenic photosynthesis
2.5 Oxygenic photosynthesis
Great oxidation event
Aerobic respiration w
idespread
Multicellular organism
s
Placental animals
Single cell organisms only Single & multicellular organisms
There are no complex
multicellular organisms that
are purely glycolytic
Anaerobic only:(glycolysis) single cells
Anaerobic +
aerobic: multicellular complexity
Koch & Britton, J. Physiology, 2008 Adobe Acrobat
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Founder Population
Generation 1
Generation 2
Generation 3
Generation 4LOW HIGH
In 1996 we started artificial divergent
selection for energy transfer capacity.
Low capacity runner = LCRHigh capacity runner = HCR
Current = Intrinsic + AdaptationalPhenotype
Sedentary Acquired by training
Exercise Capacity Can Be Operationally Divided Into Two
Components.
Energy transfer capacity was estimated from a speed-ramped treadmill run to exhaustion
Assessed for Intrinsic capacity
Not trained capacity
5
10
15
20
25
30
-5 0 5 10 15 20 25 30 35Duration of Run (min)
Spee
d (m
/min
)
Speed-Ramped ProtocolStart = 10 m/minIncreased 1 m every 2 min
N:NIH as founder population
Rat equivalent of the
Bruce Protocol
Yu-yu Ren, Katherine Overmyer, Nathan Qi, Mary Treutelaar, Lori Heckenkamp, Molly Kalahar, Lauren Koch, Steven Britton, Charles Burant, Jun Li , PLOS ONE, 2013
1996 2014
~ 14,000 rats
Adobe Acrobat Document
HCR
LCR
The proportion of total running performance that is due to the additive effects of genes is about 40% in each line.
[h2 or narrow sense heritability]
Heritability estimates for maximal running distance (G1-G28)
Line SOLAR* WOMBAT*
HCR 0.44 ± 0.02 0.45 ± 0.08
LCR 0.39 ± 0.02 0.41 ± 0.06
Yu-yu Ren University of Michigan Jun Li Human Genetics
*Modern variants of: Average information algorithm and Spatial matrix Residual Maximum Likelihood (ASreml) software
Heritability
Longevity & Aging
(Karvinen & Kainulainen)
Phosphorylating respiration
(Kainulainen, Hawley)
Fatty liver disease
(Thyfault)
Post-surgerycognitive decline
(Mervyn Maze)
Metabolic syndrome(Wisloff)
Activity (NEAT)(Levine & Novak)
Cardiac stress
signaling(Burniston)
Alzheimer’s-likeneurodegeneration
(Russell)
Intra-cerebral hemorrhage(Keep & Hua)
Metabolic flexibility(Evans & Burant)
Susceptibility to cancer
(Thompson)
Hippocampal Neurogenesis
(Tognoni & Williams)
LCR relative to HCR display
High runners live longerSurvival Curves (n= 23 LCR n= 23 HCR)
24months
34.7months
(From Lauren Koch……Ulrik Wisloff et. al, Circulation Research, 2011)Adobe Acrobat
Document
VO2max predicted time of death both between strains and for each rat within strain.
Exercise Capacity = Innate + Adaptive
Rat Model #2Low Response Trainers - LRTHigh Response Trainers - HRT
Exercise Capacity Can Be Divided Into Two Components.
-In the large sense-
We do not have explanation for how (apparently) disparate clinical conditions associate with low aerobic exercise capacity.
For interpretation we synthesize ideas from Hans Krebs, Peter Mitchell, and Ilya Prigogine about non-equilibrium thermodynamics and entropy (order from disorder).
-Succinctly-
Summary of Prigogine’s conclusions:
1. Systems tend to organize to a higher complexity when the resulting system can dissipate energy faster than the independent parts.
2. Entropy can temporarily decrease and ordered systems can form (order from disorder).
Interpreting through Ilya Prigogine is our new challenge. (a non-equilibrium thermodynamic lens)
Nobel Prize: Chemistry 1977"for his contributions to understanding
energy dispersal and complexity”
Condensed statement:
1) evolution was underwritten by obligatory energy dissipation mechanisms (entropy).
2) emergence of complexity was coupled to the high energetic nature of oxygen metabolism.
These statements form the basis for the Energy Transfer Hypothesis:
“Variation in capacity for energy transfer is a central mechanistic determinant of the divide between disease and health.”
-Selection for low and high exercise capacity was an unbiased test of this hypothesis-
Evolution Energy metabolism Energy dissipation
┼ ┼
Krebs Mitchell Prigogine
These contrasting rat model systems are maintained as an international resource by:
Department of AnesthesiologyUniversity of Michigan
and National Institutes of Health
United States Department of Health and Human Services
Low Capacity Runner (LCR) High Capacity Runner (HCR)
Low Response Trainer (LRT) High Response Trainer (HRT)
Contact Steven Britton or Lauren Koch at the University of Michigan for availability of these rats for study
Exercise Capacity = Innate + Adaptive
Rat Model #2Low Response Trainers - LRTHigh Response Trainers - HRT
Exercise Capacity Can Be Divided Into Two Components.
In 1999 the HERITAGE Family Study provides initial information about the large inter-individual variation in
response to exercise training.
Bouchard et al., J. Appl. Physiol. 87(3), 1999
V)VO2max
Low responders
Highresponders
Twin and familial studies show a significant genetic component.
Δ V
O2m
ax (m
l/min
)
-600-400-200
0200400600800
1000
25 50 75 100
Foundern=152
Percentile
D
IST,
met
ers
Wide variation for response to training in N:NIH genetically diverse rats
Population mean = +140 m
Koch et al., Physiol Gen. 2013
Generation 15n=178
-600-400-200
0200400600800
1000
25 50 75 100Percentile
D
IST,
met
ers
Mean for HRT = +223 m
-65 m = Mean for LRT
Selection produced populations of Low Response Trainers (LRT ) and
High Response Trainers (HRT).
Koch et al., Physiol Gen. 2013
8 min longer
2.5 min less
Blunted CardiomyocyteRemodeling Response inExercise-Resistant Rats
Ulrik Wisloff......>>......Lauren Koch, 2015
Wisloff et al., 2015
end
Miami Nature Winter Symposia, 2003. Celebration of 50th year of the“Double Helix.”Jim Watson to Lauren Koch: “If you go after something big, everyone will try to make you feel bad.”
Miami Nature Winter Symposia, 2003. Celebration of 50th year of the“Double Helix.”
Koch, Watson, Britton, Irene Wolf
Ju Li, Yu-Yu Ren, Steve Britton, Jonathon FlintCold Spring Harbor Laboratory, December, 2013