Cortisol acting through the glucocorticoid receptor is not involved in exercise-enhanced growth, but does affect the white skeletal muscle transcriptome in zebrafish (danio rerio)

Forced sustained swimming exercise at optimal speed enhances growth in many fish species, particularly through hypertrophy of the white skeletal muscle. The exact mechanism of this effect has not been resolved yet. To explore the role of cortisol, we first subjected wild-type zebrafish to an exercise protocol validated for exercise-enhanced growth, and showed that exercised zebrafish, which indeed showed enhanced growth, had higher cortisol levels than the non-exercised controls. A central role was therefore hypothesized for the steroid hormone cortisol acting through the Glucocorticoid receptor (Gr). Second, we subjected wild-type zebrafish and zebrafish with a mutant Gr to exercise at optimal, suboptimal, and super-optimal speeds and compared them with non-exercised controls. Exercised zebrafish showed growth enhancement at all speeds, with highest growth at optimal speeds. In the Gr mutant fish, exercise resulted in growth enhancement similar to wild-type zebrafish, indicating that cortisol signaling through Gr cannot be considered as a main determinant of exercise-enhanced growth. Finally, the transcriptome of white skeletal muscle tissue was analyzed by RNA sequencing. The results of this analysis showed that in the muscle tissue of Gr mutant fish a lower number of genes is regulated by exercise than in wild-type fish (183 vs. 351). A cluster of 36 genes was regulated by exercise in both wild-type and mutant fish, and in this cluster genes involved in transcriptional regulation and protein ubiquitination were overrepresented. Because these two processes appear to be regulated in both wild type and mutant fish, which both display exercise-enhanced growth, we suggest that they play an important role in the growth of muscles upon exercise.