Rat models of complex disease and evolution of metazoan complexity

Abstract

We suggest a unified view that oxygen metabolism underlies mechanistically major aspects of the evolution of complexity, and thus by default, complex disease. This view is based upon connecting two generalities. First, geochemical and fossil records support the notion that atmospheric oxygen is unique for the evolution of metazoan complexity (Science 309, 2202). Second, clinical observations demonstrate a strong statistical association between aerobic capacity and all-cause mortality (N. Eng. J. Med, 346, 793). From these ideas, we hypothesized that artificial selection of rats for low and high aerobic exercise capacity would yield models that contrast for the divide between health and disease. In 1996 we started large-scale selective breeding to develop strains of rats that contrast for intrinsic (i.e., untrained) aerobic treadmill running capacity. After eleven generations of selection, the low capacity runners (LCR) and high capacity runners (HCR) differed by over 300% in aerobic running capacity. The LCR scored higher on cardiovascular risks and features of the metabolic syndrome, including higher blood pressure, insulin, random glucose,fasting glucose, free fatty acids, visceral fat, and triglycerides. The HCR were higher for health factors such as maximal oxygen consumption, heart function, nitric oxide formation in arteries, economy of oxygen use, and abundance of proteins required for mitochondrial function in skeletal muscle (Science 307, 418). These rats represent potentially useful models for unraveling the genetic and environmental causes of complex disease at all levels of biologic organization. Supported by NIH grants HL64270 and RR17718.