Regulation of stress-activated protein kinases by exercise and contraction in skeletal muscle

Thesis (Sc.D.)--Boston UniversityPLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.The c-Jun NH2-terminal kinase (JNK) and p38 intracellular signaling cascades are mitogen-activated protein kinase (MAPK) signaling pathways that are activated in mammalian cells by a variety of stressors, including proinflammatory cytokines, osmotic shock, and shear stress. The purpose of this dissertation research was to examine the effect of injury-producing exercise on JNK and p38 activities in human skeletal muscle and to determine whether mechanical stress is a primary stimulator of JNK and p38 activities with contraction. Twelve healthy subjects (7M/5F) completed maximal concentric or eccentric knee extensions on an isokinetic dynamometer (10 sets, 10 reps). Needle biopsies were obtained from the vastus lateralis muscle 24 h before exercise, immediately post-exercise, and 6 h post-exercise. While both forms of exercise increased JNK activity immediately post-exercise, eccentric contractions resulted in a much higher activation (15-fold vs. 4-fold increase above basal for eccentric and concentric, respectively). By 6 h post-exercise, JNK activity decreased back to baseline values. In a separate study, 14 male subjects completed a 42.2 km marathon. Biopsies were obtained from the vastus lateralis muscle 10 days prior to the marathon, immediately following the race, and 1, 3, and 5 days after the race. JNK activity increased 7-fold over basal immediately postexercise, but decreased back to basal 1, 3, and 5 days after the exercise. The activity of p38y also was increased and decreased in a similar pattern. However, no regulation was observed for p38α. In a third study, the effects of contraction and static stretch on JNK activity and p38 phosphorylation were determined in the rat soleus muscle in vitro. Static stretch dramatically increased JNK activity and p38 phosphorylation, whereas isometric contraction resulted in much smaller increases in JNK activity and p38 phosphorylation. The regulation of focal adhesion proteins also was examined following both exercise and contraction. The work presented in this thesis demonstrates that injury-producing exercise results in the marked activation of the JNK and p38 stress-activated protein kinases and provides evidence that mechanical stress may be a major contributor to increases in JNK and p38 activities observed following contraction in rat and human skeletal muscle.2031-01-0