Rac1 and AMPK Account for the Majority of Muscle Glucose Uptake Stimulated by Ex Vivo Contraction but Not In Vivo Exercise

Exercise bypasses insulin resistance to increase glucose uptakein skeletal muscle and therefore represents an important alternative to stimulate glucose uptakein insulin-resistant muscle. Both Rac1and AMPKhave been shown to partly regulate contraction-stimulated muscle glucose uptake, but whether those two signaling pathways jointly account for the entire signal to glucose transportis unknown. We therefore studied the ability of contraction and exercise to stimulate glucose transportin isolated muscles with AMPKloss of function combined with either pharmacological inhibition or genetic deletion of Rac1. Muscle-specific knockout (mKO) of Rac1, a kinase-dead α2 AMPK(α2KD), and double knockout (KO) of β1 and β2 AMPKsubunits (β1β2 KO) each partially decreased contraction-stimulated glucose transportin mouse soleus and extensor digitorum longus (EDL) muscle. Interestingly, when pharmacological Rac1inhibition was combined with either AMPKβ1β2 KO or α2KD, contraction-stimulated glucose transportwas almost completely inhibited. Importantly, α2KD+ Rac1mKO double-transgenic mice also displayed severely impaired contraction-stimulated glucose transport, whereas exercise-stimulated glucose uptakein vivo was only partially reduced by Rac1mKO with no additive effect of α2KD. It is concluded that Rac1and AMPKtogether account for almost the entire ex vivo contraction response in muscle glucose transport, whereas only Rac1, but not α2 AMPK, regulates muscle glucose uptakeduring submaximal exercise in vivo.