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Review
. 2012 Feb;22(2):29-34.
doi: 10.1016/j.tcm.2012.06.007. Epub 2012 Aug 4.

A rat model system to study complex disease risks, fitness, aging, and longevity

Lauren Gerard Koch  1 , Steven L Britton, Ulrik Wisløff
Affiliations
Review

A rat model system to study complex disease risks, fitness, aging, and longevity

Lauren Gerard Koch et al. Trends Cardiovasc Med. 2012 Feb.

Abstract

The association between low exercise capacity and all-cause morbidity and mortality is statistically strong yet mechanistically unresolved. By connecting clinical observation with a theoretical base, we developed a working hypothesis that variation in capacity for oxygen metabolism is the central mechanistic determinant between disease and health (aerobic hypothesis). As an unbiased test, we show that two-way artificial selective breeding of rats for low and high intrinsic endurance exercise capacity also produces rats that differ for numerous disease risks, including the metabolic syndrome, cardiovascular complications, premature aging, and reduced longevity. This contrasting animal model system may prove to be translationally superior relative to more widely used simplistic models for understanding geriatric biology and medicine.

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Figures

Figure 1
Figure 1
Positive health environments reversed complex disease risk in low capacity runner (LCR) rats. (A) Caloric restriction (CR) reduced body mass (A) in LCR to reach the equivalent of HCR on ad libitum (AL) feeding and improves glucose (B) and insulin (C) tolerance compared to AL-LCR. (Figure 1A-C is reprinted from Bowman et al: 2010. Caloric restriction reverses hepatic insulin resistance and steatosis in rats with low aerobic capacity. Endocrinology, 151(11), 5157– 64. Copyright 2010, The Endocrine Society). (D) Maximal oxygen uptake (VO2max) increased more with aerobic interval trainig (AIT) relative to continuous moderate exercise (CME) in LCR. Significantly different between AIT and CME (*, P < 0.05). Significantly different from sedentary (SED) (§, P< 0.01; #, P< 0.05). Figure D is reprinted from Haram et al: 2009. Aerobic interval training vs. continuous moderate exercise in the metabolic syndrome of rats artificially selected for low aerobic capacity. Cardiovascular Research, 81(4):723–3 by courtesy from The European Society of Cardiology. (E) Exercise training increased the protein content of several important regulators of carbohydrate and lipid metabolism in skeletal muscle of LCR. The protein content for nuclear orphan receptor Nur77, quantified using Western blot analysis, is shown for LCR compared to high capacity runners (HCR) in the sedentary (SED) and exercise trained (EXT) conditions. Figure E is reprinted from Lessard et al:2011. Exercise training reverses impaired skeletal muscle metabolism induced by artificial selection for low aerobic capacity. Am J Physiol by courtesy from The American Physiological Society.
Figure 2
Figure 2
Cardioventricular myocytes were more compromised in low capacity runner (LCR) compared to high capacity runner (HCR) as a function of aging. Shown here are results for adult rats (15–20 months) compared to rats at old age (25 months). Markers of pathological morphology for the LCR include: (A) increased cell length and cell width, (B) reduced transverse (T)-tubule density quantified from images stained with Di-8-ANEPP, and (C) degeneration/necrosis in light micrographs (hematoxylin and eosin stain) of myocardium in old LCR but not in old HCR; vacuoles are marked with arrowsand interstitial fibroplasia marked by letter F (bar=50 μm). Dynamic functional properties of myocytes were also more diminished in LCR versus HCR as a function of aging and included: (D) reduced isolated fractional shortening and increased time to 50% re-lengthening, (E) lessened amplitude of systolic Ca2+ transients, and (F) reduction in Ca2+spark frequency: images are confocal micrographs from quiescent cells. (Figure 2 is reprinted by courtesy from the American Heart Association. Koch et al.: 2011. Intrinsic aerobic capacity sets a divide for aging and longevity. Circ Res, 109, 1162–72).
Figure 3
Figure 3
A. Survival curves for data combined from aerobic rats at generations 14, 15, and 17 (n= 63 LCR and n= 76 HCR). Hazard ratio indicates rate of death in LCR rats was almost 6 times greater than for HCR. B. VO2max measured at 15, 20, and 25 months of age was a strong predictor of survival for rats. C. Distance run to exhaustion estimated at 3, 14, and 21 months of age was a significant, but less strong predictor of survival, relative to VO2max for HCR, but not for LCR rats. Summed, Figure 3 data represent the first demonstration that longevity can segregate with an almost purely intrinsic aerobic endurance phenotype. (Figure 3 is reprinted by courtesy from the American Heart Association. Koch et al.: 2011. Intrinsic aerobic capacity sets a divide for aging and longevity. Circ Res, 109, 1162–72.)
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References

    1. AKAR FG, AON MA, TOMASELLI GF, O'ROURKE B. The mitochondrial origin of postischemic arrhythmias. J Clin Invest. 2005;115:3527–35. - PMC - PubMed
    1. BALDWIN JE, KREBS H. The evolution of metabolic cycles. Nature. 1981;291:381–2. - PubMed
    1. BOUCHARD C, DIONNE FT, SIMONEAU JA, BOULAY MR. Genetics of aerobic and anaerobic performances. Exerc Sport Sci Rev. 1992;20:27–58. - PubMed
    1. BOWMAN TA, RAMAKRISHNAN SK, KAW M, LEE SJ, PATEL PR, GOLLA VK, BOUREY RE, HARAM PM, KOCH LG, BRITTON SL, WISLOFF U, LEE AD, NAJJAR SM. Caloric restriction reverses hepatic insulin resistance and steatosis in rats with low aerobic capacity. Endocrinology. 2010;151:5157–64. - PMC - PubMed
    1. BURGHARDT PR, FLAGEL SB, BURGHARDT KJ, BRITTON SL, GERARD-KOCH L, WATSON SJ, AKIL H. Risk-assessment and coping strategies segregate with divergent intrinsic aerobic capacity in rats. Neuropsychopharmacology. 2011;36:390–401. - PMC - PubMed

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