Lauren Gerard Koch Functional Genomics Laboratory Medical College of Ohio Toledo, Ohio A Genome Scan for Aerobic Running Capacity QTLs in Rats

Rat Genetic Models of Aerobic Running Capacity “A Parallel Strategy” Identify already-available inbred strains that widely differ in aerobic capacity to serve as genetic models.

Aerobic Capacity was Assessed By Treadmill Running To Exhaustion In 11 Inbred Rat Strains DA and COP showed the widest divergence [Barbato et al, J. Appl. Physiol., 1998] DISTANCE RUN (meters)

70 mm Hg Langendorff-Neely Working Heart Preparation Cardiac Performance as a Likely Determinant Phenotype for Differences in Aerobic Capacity PRE-LOAD 15 mm Hg AFTER- LOAD 70 mm Hg

Cardiac Output Versus Distance Run y = 19.03X r = ISOLATED CARDIAC OUTPUT (ml/min/g Heart Weight) DISTANCE RUN (METERS) PVG DA AUG SR F344 ACI LEW WKY BUF MNS COP [Barbato et al, J. Appl. Physiol., 1998]

Based on these data, we propose that COP and DA strains could serve as parentals for developing a segregating population for the evaluation of the genetic basis of low and high exercise capacity.

COP DA

COPF1F1 DA

COP F2F2 F1F1 DA

Genome-Wide Scan for Aerobic Capacity QTLs. Phase I: Selective Genotyping of F 2 (COP X DA) Population

LOD Plot for Chromosome 16 Phase II: Entire F 2 (COP X DA) Population Significant QTL

LOD Plot for Chromosome 3 Phase II: Entire F 2 (COP X DA) Population

Interaction Effect Between Markers D16Rat55 and D3Rat56 on Distance Run

Additional interval mapping was done to determine whether heart weight and body weight QTLs co-localize to aerobic capacity regions.

Relative Heart Weight QTL Chromosome 7 Aerobic Capacity- Phase I

Total Heart Weight QTL Chromosome 8

Body Weight QTL Chromosome 8 Aerobic Capacity- Phase I

QTL Regions contain genes related to Lipid Metabolism and Energy Homeostasis Chromosome 16 Lipoprotein Lipase (Lpl) Neuropeptide Y5 (Npy5r) Adrenergic Beta 3 (Adrb3) Carboxypeptidase E (Cpe) Chromosome 7 Peroxisome Proliferator- Activated Receptors (Ppara) Chromosome 3 Carboxyl Ester Lipase (Cel) Retinoid X Receptor (Rxra) Chromosome 8 Apolipoprotein (Apoc3, Apoa1, APoa4) Hepatic Lipase (Lipc) 5´Nucleotidase (Nt5)

There are at least two aerobic capacity QTLs present on rat chromosome 16. A QTL near D16Rat17 had effects on running capacity independent of other putative QTLs whereas the aerobic capacity QTL located near D16Rat55 interacted with a QTL located near D3Rat56. Possible associated relative heart weight, total heart weight, and average body weight QTLs were found on chromosomes 7 (D7Rat74) and 8 (D8Rat23) respectively. Candidate genes within the identified QTL regions include enzymes and transcription factors involved in energy balance and lipid metabolism. Summary

Significance These findings represent the first known identification of aerobic capacity QTLs in animal genetic models. This work will be appear as the cover article in the June issue of Genomics.

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Putative Aerobic Capacity QTLs for F 2 (COP x DA) Population

We found other Likely Determinant Phenotypes where DA is Significantly Greater than COP: 1.Maximal developed tension in isolated papillary muscles (38%) (Chen et al., J. Physiol., 2001). 2.Fractional Shortening (50%) and amplitude of calcium transients (78%) in ventricular myocytes (Chen et al., J. Physiol., 2001). 3.Wider range for sympathetic and parasympathetic control of heart rate and blood pressure (Koch et al., Physiol. Genomics, 1999). 4.Heart weight to body weight ratio (27%) (Koch et al., Physiol. Genomics, 1999). 5.Cardiac adenosine production (46%) (Walker et al., Am J. Physiol., 2002).

Phenotype Data for Aerobic Treadmill Running Capacity in Development of an F 2 (COP x DA) Population X

Biesiadecki et al., Am J. Physiol.,1999