Immobilization depresses insulin signaling in skeletal muscle

Prolonged immobilization depresses insulin-induced glucose transport in ske letal muscle and leads to a catabolic state in the affected areas, with res ultant muscle wasting. To elucidate the altered intracellular mechanisms in volved in the insulin resistance, we examined insulin-stimulated tyrosine p hosphorylation of the insulin receptor beta -subunit (IR-beta) and insulin receptor substrate (IRS)-1 and activation of its further downstream molecul e, phosphatidylinositol 3-kinase (PI 3-K), after unilateral hindlimb immobi lization in the rat. The contralateral hindlimb served as control. After 7 days of immobilization of the rat, insulin was injected into the portal vei n, and tibialis anterior muscles on both sides were extracted. Immobilizati on reduced insulin-stimulated tyrosine phosphorylation of IR-beta and IRS-1 . Insulin-stimulated binding of IRS-1 to p85, the regulatory subunit of PI 3-K, and IRS-1-associated PI 3-K activity were also decreased in the immobi lized hindlimb. Although IR-beta and p85 protein levels were unchanged, IRS -1 protein expression was downregulated by immobilization. Thus prolonged i mmobilization may cause depression of insulin-stimulated glucose transport in skeletal muscle by altering insulin action at multiple points, including the tyrosine phosphorylation, protein expression, and activation of essent ial components of insulin signaling pathways.