Selection-, age-, and exercise-dependence of skeletal muscle gene expression patterns in a rat model of metabolic fitness.

Intrinsic aerobic exercise capacity can influence many complex traits including obesity and aging. To study this connection we established two rat lines by divergent selection of untrained aerobic capacity. After 32 generations the high capacity runners (HCR) and low capacity runners (LCR) differed in endurance running distance and body fat, blood glucose, other health indicators, and natural life span. To understand the interplay among genetic differences, chronological age, and acute exercise we performed microarray-based gene expression analyses in skeletal muscle with a 2×2×2 design to simultaneously compare HCR and LCR, old and young animals, and rest and exhaustion. Transcripts for mitochondrial function are expressed higher in HCRs than LCRs at both rest and exhaustion and for both age groups. Expression of cell adhesion and extracellular matrix genes tend to decrease with age. This and other age effects are more prominent in LCRs than HCRs, suggesting that HCRs have a slower aging process and this may be partly due to their better metabolic health. Strenuous exercise mainly affects transcription regulation and cellular response. The effects of any one factor often depend on the other two. For example, there are ∼140 and ∼110 line-exercise "interacting" genes for old and young animals, respectively. Many genes highlighted in our study are consistent with prior reports, but many others are novel. The gene- and pathway-level statistics for the main effects, either overall or stratified, and for all possible interactions, represent a rich reference dataset for understanding the interdependence among lines, aging, and exercise.