Theoretical and Biological Evaluation of the Link between Low Exercise Capacity and Disease Risk

Abstract

Large-scale epidemiological studies show that low exercise capacity is the highest risk factor for all-cause morbidity and mortality relative to other conditions including diabetes, hypertension, and obesity. This led us to formulate the energy transfer hypothesis (ETH): Variation in capacity for energy transfer is the central mechanistic determinant of the divide between disease and health. As a test of this hypothesis, we predicted that two-way selective breeding of genetically heterogeneous rats for low and high intrinsic treadmill running capacity (a surrogate for energy transfer) would also produce rats that differ for disease risks. The lines are termed low-capacity runners (LCRs) and high-capacity runners (HCRs) and, after 36 generations of selection, they differ by more than eightfold in running capacity. Consistent with the ETH, the LCRs score high for developing disease risks, including metabolic syndrome, neurodegeneration, cognitive impairment, fatty liver disease, susceptibility to cancer, and reduced longevity. The HCRs are resistant to the development of these disease risks. Here we synthesize ideas on nonequilibrium thermodynamics and evolution from Ilya Prigogine, Hans Krebs, and Peter Mitchell to formulate theoretic explanations for the ETH. First, at every moment in time, the atoms and molecules of organisms are reorganizing to pursue avenues for energy transfer. Second, this continuous organization is navigating in a constantly changing environment such that "strategies" are perpetually in flux and do not leave a simple footprint (evolution). Third, as a consequence, human populations demonstrate a wide variation in capacity for energy transfer that mirrors mechanistically the divide between disease and health.

Figure 1.

Running and genetic distance changes as a function of divergent selection. (A) Response to selection for 28 generations. Each symbol represents the distribution of running distance for each generation in each line. The symbols for each generation combine box plots and kernel density plots to depict the observed probability density. Males and females combined (n = 11,442 rats). NIH:H are the genetically heterogeneous founder stock rats. (B) Estimate of genetic “distance” between low-capacity runner (LCR) and high-capacity runner (HCR) lines. Multidimensional scaling showed that genetic distance between the lines increased across generations 5, 14, and 26. Dimension 1 = LCR-HCR lines, and dimension 2 = generation. Dimension estimates for 142 rats shown. (A, From Ren et al. 2013; reprinted, with permission, from the authors.)

Figure 2.

Visualization of possible changes in entropy (dS) across time from the big bang (lowest entropy) to equilibrium (highest entropy). dS = d_eS + d_iS, where d_eS is the flow of entropy caused by exchanges with the surroundings (environment), and d_iS is the entropy production as a result of processes inside the system, such as diffusion, chemical reactions, and heat conduction (internal metabolism) (Prigogine 1978).

Figure 3.

Energy dissipation leading to organization that can dispel energy even more effectively seems to be the fundamental property of matter in response to an external energy transfer. Four examples are easy to envision. (A) A schematic cross section of a tropical cyclone. A cyclone is a meteorological system driven by a temperature contrast between the hot tropical sea surface and the cold top of the tropopause in which ordered convection cells form that mediate more efficient dissipation of energy. (B) Stellar nucleosynthesis is the process within stars that forms new atomic nuclei from the accretive fusion of preexisting protons and neutrons. Depicted is the layering of element formation. As temperature increases toward the center of a star, heavier elements are formed. Iron (Fe) is formed at the center of stars and elements heavier than Fe require the higher energy of supernovae for formation. (C) Bénard cell formation is a type of motion that occurs in a thin liquid layer between two horizontal plates when a heat flow is imposed from below (T₂). When the heat flux reaches a critical value (T₁ < T₂), the fluid becomes coherent and convective. Structured (ordered) coherent hexagonal-shaped cells emerge that increase the rate of heat transfer and gradient destruction in the system (disorder). (D) Thermodiffusion. Consider a closed system containing hydrogen (H) and nitrogen (N). At uniform temperature (T5 = T5), there will be a random distribution of these two gases. If a temperature gradient is imposed (T10 > T5), hydrogen will move to the hotter side and nitrogen to the cooler. Here, entropy production is associated with a heat flow–producing disorder and it is also simultaneously associated with a more ordered condition of the gases.

Figure 4.

In 1961, Peter Mitchell published his landmark manuscript entitled “Coupling of Phosphorylation to Electron and Hydrogen Transfer by a Chemi-Osmotic Type of Mechanism.” In the last paragraph of this paper, he declares that transport and metabolism may be conceived of as the “same process.” We extended this idea to speculate that the H⁺ diffusion can be considered an “inanimate” step within evolution that couples to the “animate” metabolic formation of ATP from ADP.

Figure 5.

Selective breeding for low and high training response to treadmill running. (A) Rats were artificially selected for the change in running capacity in response to 8 weeks of training. Depicted is the training response for each of the 152 founder population rats. The horizontal brackets indicate the lowest and highest 10th percentile animals that were used as founders to start the low-response trainer (LRT) and high-response trainer (HRT) selected lines. (From Koch et al. 2013; reprinted, with permission, from the authors.) (B) The changes in running capacity with training for LRT rats (light colored bars) and HRT rats (dark bars) after 15 generations of training. Selection had caused marked divergence in training response between the lines. (C) Maximal oxygen consumption (VO_2max) measured before and after 8 weeks of high-intensity aerobic interval training in LRT rats. Training failed to produce VO_2max changes in LRTs. (D) High-intensity training produced on average a 40% increase in VO_2max in HRTs. (From Wisloff et al. 2015; reprinted, with permission; from Elsevier © 2015.)