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Muscle responses to exercise are complex and include acute responses to exercise-induced injury, as well as longer term adaptive training responses. Using Alaskan sled dogs as an experimental model, changes in muscle gene expression were analyzed to test the hypotheses that important regulatory elements of the muscle's adaptation to exercise could be identified based on the temporal pattern of gene expression. Dogs were randomly assigned to undertake a 160-km run (n = 9), or to remain at rest (n = 4). Biceps femoris muscle was obtained from the unexercised dogs and two dogs at each of 2, 6, and 12 h after the exercise, and from three dogs 24 h after exercise. RNA was extracted and microarray analysis used to define gene transcriptional changes. The changes in gene expression after exercise occurred in a temporal pattern. Overall, 569, 469, 316, and 223 transcripts were differentially expressed at 2, 6, 12, and 24 h postexercise, respectively, compared with unexercised dogs (based on P ≣ 0.01 and an absolute fold change of ≥ 1.5). Increases in a number of known transcriptional regulators, including peroxisome proliferator-activated receptor-α, cAMP-responsive element modulator, and CCAAT enhancer binding protein-δ, and potential signaling molecules, including brain-derived neurotrophic factor, dermokine, and suprabasin, were observed 2 h after exercise. Biological functional analysis suggested changes in expression of genes with known functional relationships, including genes involved in muscle remodeling and growth, intermediary metabolism, and immune regulation. Sustained endurance exercise by Alaskan sled dogs induces coordinated changes in gene expression with a clear temporal pattern. RNA expression profiling has the potential to identify novel regulatory mechanisms and responses to exercise stimuli. [ABSTRACT FROM AUTHOR]