Genetic determinants of voluntary exercise

Abstract

Variation in voluntary exercise behavior is an important determinant of long-term human health. Increased physical activity is used as a preventative measure or therapeutic intervention for disease, and a sedentary lifestyle has generally been viewed as unhealthy. Predisposition to engage in voluntary activity is heritable and induces protective metabolic changes, but its complex genetic/genomic architecture has only recently begun to emerge. We first present a brief historical perspective and summary of the known benefits of voluntary exercise. Second, we describe human and mouse model studies using genomic and transcriptomic approaches to reveal the genetic architecture of exercise. Third, we discuss the merging of genomic information and physiological observations, revealing systems and networks that lead to a more complete mechanistic understanding of how exercise protects against disease pathogenesis. Finally, we explore potential regulation of physical activity through epigenetic mechanisms, including those that persist across multiple generations.

Figure 1

The predisposition to engage in voluntary exercise is complex and simultaneously effected by genetic architecture, the environment, and gene-environment and gene-gene interactions. Both genetic architecture and the environment are comprised of multiple components with the relative influence of each varying. Here, we have attempted to depict only a fraction of the environmental components, with the primary focus intended to be the genetic regulation of physical activity as described in the text. We have provided example references (black boxes) of each of the effects shown.

Figure 2

Data from [23] depicting QTL underlying the temporal pattern of voluntary activity as well as the trajectory of activity across the entire 6 day wheel access period. Suggestive (P ≤ 0.1) or significant (P ≤ 0.05) peaks imply unique genomic regions are least partially responsible for the initiation, continuation, and temporal pattern of exercise. For example, regions on chromosome 1 have been shown to harbor genes involved in anxiety-like behavior in rodents. Therefore, fear, or general anxiety may contribute to wheel running during initial exposure to wheels (days 1–2), with the daily routine of exercise governed by distinct loci (days 4–6). And, finally, the exercise trajectory over time (slope across days 1–6) is regulated by still another unique genomic region. Pictorially, the background photographs represent each of these phenomena. Photographs provided by Jason Smith, University of North Carolina – Chapel Hill.

Figure 3

Schematic illustration of creation of the Collaborative Cross (CC) and Diversity Outbred (DO) mouse populations, two next-generation mouse models developed through balanced crossing of 8 progenitor inbred strains, including several of wild origin. Whereas CC lines represent new recombinant inbred strains, the DO [39] is derived from progenitor lines of the Collaborative Cross [93] and is maintained by a randomized outbreeding strategy. Thus the DO and CC populations capture the same set of natural allelic variants derived from a common set of eight founder strains, but the DO is maintained as an outbred population (with heterozygosity) while the CC is maintained as an inbred population. Although the DO is an ideal resource for high-resolution genetic mapping, the CC can provide predictive validation of mapping results obtained with the DO, as well as a source of reproducible genotypes for mechanistic studies [30]. Both of these populations exhibit dramatic phenotypic variability for voluntary exercise with extensive transgressive variation. Average wheel-running distances for A) male pre-CC and founder line males on days 5 and 6. Group means for each founder line are indicated in black with appropriate color-coded asterisk above to indicate strain being depicted. B) Average wheel-running distances for DO male and female mice on days 5 and 6. The original figure showing the color coded mosaic structure of the DO and CC is from Gary Churchill and Karen Svenson (The Jackson Laboratory). The original figure (A) is from [16]. Data used to generate the figure (B) is unpublished (provided by Daniel Pomp).

Figure 4

Murine models have been utilized to show heritability of the predisposition to engage in voluntary exercise (Fig. 1 in [94]; see also [22]) with epistatic interactions accounting for a considerable amount of genetic variation within a population (Fig. 1A in [34]). Furthermore, it has been demonstrated that the biological basis of voluntary exercise is composed of both ability, as illustrated through exercise mimetics (Fig. 3 in [75]), and motivation, supported via the identification of brain expression quantitative trait loci, or brain eQTL) (Fig. 3B in [45]). The original individual figures are from [34,45,75,94]. Composite image was designed and created by Mark A. Schmitter, Ohio Wesleyan University.