Immobilization rapidly induces muscle insulin resistance together with the activation of MAPKs (JNK and p38) and impairment of AS160 phosphorylation.

Acute short-duration physical inactivity induces the development of insulin resistance for glucose uptake in skeletal muscle. We examined the possibility that inactivity rapidly induces muscle insulin resistance via the excessive activation of proinflammatory/stress pathways including those of IKK/IκB/NF-κB, JNK, and p38 MAPK We also examined the other possibility that inactivity-induced rapid development of insulin resistance is associated with reduced phosphorylation of AS160, the most distal insulin-signaling protein that have been linked to the regulation of glucose uptake. Male Wistar rats were subjected to unilateral hindlimb immobilization for 6 h. At the end of the immobilization, the soleus muscles from both immobilized and contralateral non-immobilized hindlimbs were dissected out. Immobilization decreased insulin-stimulated 2-deoxyglucose uptake in rat soleus muscle within 6 h. This rapid development of insulin resistance was accompanied by elevated phosphorylation of both JNK and p38 (commonly used indicator of JNK and p38 pathway activity, respectively). In addition, the abundance of SPT2, a rate-limiting enzyme regulating ceramide biosynthesis, was increased in immobilized muscle. Immobilization did not alter the abundance of IκBα (commonly used indicator of IKK/IκB/NF-κB pathway activity). The basal phosphorylation of AS160 at Thr642 and Ser588 was decreased together with the development of insulin resistance. These results suggest the possibility that inactivity-induced rapid development of insulin resistance in immobilized muscle is related to enhanced activation of JNK and/or p38. Elevated ceramide biosynthesis pathway may contribute to this activation. Our results also indicate that decreased basal phosphorylation of AS160 may be involved in inactivity-induced insulin resistance.