Based upon the strong statistical association between aerobic capacity and all-cause morbidity and mortality, it was hypothesized that artificial selection of rats for low and high aerobic exercise capacity would yield models that also contrast for disease risks. If true, this would support the notion that impaired oxygen metabolism is a common feature that mechanistically underlies disease risks. Twenty generations of bidirectional selection produced lines of low capacity runners (LCR) and high capacity runners (HCR) that differ by over 5-fold in aerobic treadmill running capacity. The LCR score high on numerous risks including the metabolic syndrome and the HCR score high for health factors such as maximal oxygen consumption. Importantly, the LCR also respond more to environmental health risks such high fat diet. The long-term goals are to understand mechanistically the features that divide these contrasting models for disease risk and to ultimately make these models an economically viable and self-sustaining resource.
The specific aims are to: 1) continue two-way artificial selection until divergence plateaus, 2) generate and phenotype LCR and HCR for mechanistic evaluation of physiologic and disease risk differences;special emphasis will be given to evaluation of differential gene expression using novel bioinformatics approaches, and, 3) stabilize genotypes within the models by producing a panel of inbred strains that represent the 5-fold divide for running capacity. We describe four large-scale studies that are being pursued aggressively as representative examples: a) mechanistic evaluation of differential for aging and longevity between LCR and HCR (Russ Hepple), b) test if exercise or caloric restriction in very young LCR or HCR has a long-term positive """"""""imprinting"""""""" effect on metabolic endpoints (Charles Burant), c) interpret the large number of expression arrays being generated with a """"""""molecular concept map"""""""" that navigates 15 databases (Arul Chinnaiyan), and 4) explore the molecular basis for higher anxiety and depression in the LCR compared to HCR (Huda Akil). The genetic and environmental variation of human populations imparts considerable difficulty to the study of complex diseases, making animal models an attractive path. The LCR and HCR are hypothesis-based models that are currently known to divide for numerous disease risks, with more likely to be defined. Information obtained from these models will immediately suggest pathways for translational studies for more effective modes of diagnosis, prevention, and treatment of complex diseases.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Resource-Related Research Projects (R24)
Project #
5R24RR017718-08
Application #
7588723
Study Section
National Center for Research Resources Initial Review Group (RIRG)
Program Officer
Harding, John D
Project Start
2008-04-01
Project End
2013-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
8
Fiscal Year
2009
Total Cost
$454,312
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Physical Medicine & Rehab
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Falegan, Oluyemi S; Vogel, Hans J; Hittel, Dustin S et al. (2017) High Aerobic Capacity Mitigates Changes in the Plasma Metabolomic Profile Associated with Aging. J Proteome Res 16:798-805
Chandrasekaran, Krish; Muragundla, Anjaneyulu; Demarest, Tyler G et al. (2017) mGluR2/3 activation of the SIRT1 axis preserves mitochondrial function in diabetic neuropathy. Ann Clin Transl Neurol 4:844-858
Burghardt, P R; Krolewski, D M; Dykhuis, K E et al. (2016) Nucleus accumbens cocaine-amphetamine regulated transcript mediates food intake during novelty conflict. Physiol Behav 158:76-84
Vieira-Potter, Victoria J; Padilla, Jaume; Park, Young-Min et al. (2015) Female rats selectively bred for high intrinsic aerobic fitness are protected from ovariectomy-associated metabolic dysfunction. Am J Physiol Regul Integr Comp Physiol 308:R530-42
Hart, Nikolett; Sarga, Linda; Csende, Zsolt et al. (2014) Resveratrol attenuates exercise-induced adaptive responses in rats selectively bred for low running performance. Dose Response 12:57-71
Gavini, Chaitanya K; Mukherjee, Sromona; Shukla, Charu et al. (2014) Leanness and heightened nonresting energy expenditure: role of skeletal muscle activity thermogenesis. Am J Physiol Endocrinol Metab 306:E635-47
Torma, Ferenc; Koltai, Erika; Nagy, Enik? et al. (2014) Exercise Increases Markers of Spermatogenesis in Rats Selectively Bred for Low Running Capacity. PLoS One 9:e114075
Choi, Joungil; Chandrasekaran, Krish; Demarest, Tyler G et al. (2014) Brain diabetic neurodegeneration segregates with low intrinsic aerobic capacity. Ann Clin Transl Neurol 1:589-604
Torma, Ferenc; Bori, Zoltan; Koltai, Erika et al. (2014) Eating habits modulate short term memory and epigenetical regulation of brain derived neurotrophic factor in hippocampus of low- and high running capacity rats. Brain Res Bull 107:54-60
Burniston, Jatin G; Kenyani, Jenna; Gray, Donna et al. (2014) Conditional independence mapping of DIGE data reveals PDIA3 protein species as key nodes associated with muscle aerobic capacity. J Proteomics 106:230-45

Showing the most recent 10 out of 86 publications