Marathon running transiently increases c-Jun NH2-terminal kinase and p38γ activities in human skeletal muscle

1. We examined the: pattern of activation and deactivation of the stress-activated protein kinase signalling molecules c-Jun NH,-terminal kinase (JNK) and p38 kinase in skeletal muscle in response to prolonged strenuous running exercise in human subjects. 2.Male subjects (n = 14; age 32 +/- 2 years; V-O2,V-max 60 +/- 2 ml kg(-1) min(-1)) completed a 42.2 km marathon (mean race time 3 h 35 min). Muscle biopsies were obtained 10 days prior to the marathon, immediattely following the race, and 1, 3 and 5 days after the race. The activation of JNK and p38, including both p38 alpha and p38 gamma, was measured with immune complex assays, The phosphorylation state of p38 (alpha and gamma) and the upstream regulators of JNK and p38, mitogen-activated protein kinase kinase 4 (MKK4) and mitogen-activated protein kinase kinase 6 (MKK6), were assessed using phosphospecific antibodies. 3. JNK. activity increased 7-fold over basal level immediately post-exercise, but decreased back to basal levels 1, 3 and 5 days after the exercise. p38 gamma phosphorylation (4-fold) and activity (1.5-fold) increased immediately post-exercise and returned to basal levels at 1, 3 and 5 days following exercise. In contrast, p38a phosphorylation and activity did not change over the time course studied. MKK4 and MKK6 phosphorylation increased and decreased in a trend similar to that observed with JNK activity and p38 gamma phosphorylation. Prolonged running exercise did not affect JNK, p38 alpha, or p38 gamma protein expression in the days following the race. 4. This study demonstrates that both JNK and p38 intracellular signalling cascades are robustly, yet transiently increased following prolonged running exercise, The differential activation of title p38 isoforms with exercise in human skeletal muscle indicates that these proteins may have distinct functions in vivo.