Contribution of nonesterified Fatty acids to mitogen-activated protein kinase activation in human skeletal muscle during endurance exercise.

Mitogen-activated protein kinase (MAPK) pathways are activated in skeletal muscle during endurance exercise, but the upstream molecular events are incompletely resolved. As an increase in plasma non-esterified fatty acids (NEFA) is a common feature of long-lasting exercise, we tested the hypothesis that NEFA contribute to the activation of MAPK during endurance exercise. Acipimox was used prior and during endurance exercise to prevent the elevation of plasma NEFA levels in healthy subjects and diabetics. In two separate studies, healthy subjects cycled for 2h and diabetics for 1h at 50% Wmax. In control conditions, plasma NEFA concentrations increased from 0.35mM to 0.90mM during exercise in healthy subjects and from 0.55mM to 0.70mM in diabetics (P<0.05). Phosphorylation state of extracellular-regulated kinase 1 and 2 (ERK1/2), p38 and, c-Jun NH2-terminal kinases (JNK) were significantly increased after exercise in the vastus lateralis in both groups. Acipimox blocked the increase in plasma NEFA concentrations and almost completely repressed any rise in ERK1/2 and p38 but not in JNK. In conclusion, our data support a role for plasma NEFA in the activation of p38 and ERK1/2 in skeletal muscle tissue of healthy and diabetic subjects during endurance exercise. Further investigation will be required to determine the molecular link between NEFA and MAPK activation during exercise in human skeletal muscle.