Muscle damage impairs insulin stimulation of IRS-1, PI 3-kinase, and Akt-kinase in human skeletal muscle

Physiological stress associated with muscle damage results in systemic insu lin resistance. However, the mechanisms responsible for the insulin resista nce are not known; therefore, the present study was conducted to elucidate the molecular mechanisms associated with insulin resistance after muscle da mage. Muscle biopsies were obtained before (base) and at 1 h during a hyper insulinemic-euglycemic clamp (40 mU . kg(-1) . min(-1)) in eight young (age 24 +/- 1 yr) healthy sedentary (maximal O-2 consumption, 49.7 +/- 2.4 ml . kg(-1) . min(-1)) males before and 24 h after eccentric exercise (ECC)-ind uced muscle damage. To determine the role of cytokines in ECC-induced insul in resistance, venous blood samples were obtained before (control) and 24 h after ECC to evaluate ex vivo endotoxin-induced mononuclear cell secretion of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-1 beta. G lucose disposal was 19% lower after ECC (P< 0.05). Insulin-stimulated insul in receptor substrate (IRS)-1 tyrosine phosphorylation was 45% lower after ECC (P< 0.05). Insulin-stimulated phosphatidylinositol (PI) 3-kinase, Akt ( protein kinase B) serine phosphorylation, and Akt activity were reduced 34, 65, and 20%, respectively, after ECC (P< 0.05). TNF-alpha, but not IL-6 or IL-1 beta production, increased 2.4-fold 24 h after ECC (P< 0.05). TNF-alp ha production was positively correlated with reduced insulin action on PI 3 -kinase (r = 0.77, P = 0.04). In summary, the physiological stress associat ed with muscle damage impairs insulin stimulation of IRS-1, PI 3-kinase, an d Akt-kinase, presumably leading to decreased insulin-mediated glucose upta ke. Although more research is needed on the potential role for TNF-alpha in hibition of insulin action, elevated TNF-alpha production after muscle dama ge may impair insulin signal transduction.