The Influence of MAP4K4 on the beneficial effects of exercise on skeletal muscle, substrate oxidation and insulin signaling

Background:

The mitogen-activated kinase kinase kinase kinase 4 (MAP4K4) is a ubiquitously expressed serine/threonine kinase. Its stimulation induces insulin resistance and specific gene polymorphisms are associated with prediabetes and insulin resistance. Moreover, MAP4K4 activity is increased in Exercise Non-Responders (NREs) failing to improve their insulin sensitivity after an exercise intervention.

Methods:

Tibialis anterior (TA) skeletal muscles from C57BL/6J mice were subjected to in vivo electroporation (IVE) in order to knockdown or overexpress the Map4k4 gene. Afterwards mice performed acute or chronic exercise protocols of treadmill exercise training. TA muscles were then analyzed via qPCR and Western Blot to determine the influence of MAP4K4 on different elements of insulin and exercise signaling.

Results:

The MAP4K4 expression depends on the diet and performed exercise protocol. On standard diet conditions and following MAP4K4 overexpression, chronic exercise leads to a reduced MAP4K4 expression, whereas on high-fat diet (HFD), the MAP4K4 expression is increased. In addition, the Myogenin expression increases after acute exercise and MAP4K4 overexpression, but decreases after chronic exercise and HFD. Moreover, we observed a reduced Ppargc1a expression after MAP4K4 knockdown.

Conclusion:

We investigated the link between MAP4K4 expression and exercise. Our results indicate that exercise affects MAP4K4 expression, depending on the exercise training performed and the diet. In contrast to the literature, MAP4K4 overexpression leads to an increased Myogenin expression, suggesting that MAP4K4 acts not as a suppressor of skeletal muscle differentiation. Further investigations will be necessary to elucidate the effect of a chronic exercise after a long-term MAP4K4 knockdown.