Dual specificity phosphatase 5 and 6 are oppositely regulated in human skeletal muscle by acute exercise

Physical activity promotes specific adaptations in most tissues including skeletal muscle. Acute exercise activates numerous signaling cascades including pathways involving mitogen‐activated protein kinases ( MAPK s) such as extracellular signal‐regulated kinase ( ERK )1/2, which returns to pre‐exercise level after exercise. The expression of MAPK phosphatases ( MKP s) in human skeletal muscle and their regulation by exercise have not been investigated before. In this study, we used mRNA sequencing to monitor regulation of MKP s in human skeletal muscle after acute cycling. In addition, primary human myotubes were used to gain more insights into the regulation of MKP s. The two ERK 1/2‐specific MKP s, dual specificity phosphatase 5 ( DUSP 5) and DUSP 6, were the most regulated MKP s in skeletal muscle after acute exercise. DUSP 5 expression was ninefold higher immediately after exercise and returned to pre‐exercise level within 2 h, whereas DUSP 6 expression was reduced by 43% just after exercise and remained below pre‐exercise level after 2 h recovery. Cultured myotubes express both MKP s, and incubation with dexamethasone (Dex) mimicked the in vivo expression pattern of DUSP 5 and DUSP 6 caused by exercise. Using a MAPK kinase inhibitor, we showed that stimulation of ERK 1/2 activity by Dex was required for induction of DUSP 5 . However, maintaining basal ERK 1/2 activity was required for basal DUSP 6 expression suggesting that the effect of Dex on DUSP 6 might involve an ERK 1/2‐independent mechanism. We conclude that the altered expression of DUSP 5 and DUSP 6 in skeletal muscle after acute endurance exercise might affect ERK 1/2 signaling of importance for adaptations in skeletal muscle during exercise.