Age-related differences in skeletal muscle insulin signaling: The role of stress kinases and heat shock proteins

Anisha A. Gupte, Gregory L. Bomhoff, Paige C. Geiger

Research output: Contribution to journalArticlepeer-review

76 Scopus citations


Aging is associated with an increase in insulin resistance in skeletal muscle, yet the underlying mechanism is not well established. We hypothesize that with aging, a chronic increase in stress kinase activation, coupled with a decrease in oxidative capacity, leads to insulin resistance in skeletal muscle. In aged (24 mo old) and young (3 mo old) Fischer 344 rats, 2-deoxyglucose uptake and insulin signaling [as measured by phosphorylation of insulin receptor substrate-1 (IRS-1), Akt (protein kinase B), and Akt substrate of 160 kDa (AS160)] decreased significantly with age. Activation of, c-Jun NH 2-terminal kinase (JNK), glycogen serine kinase-3β (GSK-3β), and degradation of IκBβ by the upstream inhibitor of kappa B kinase (IKKβ), as measured by Western blot analysis, were increased with age in both soleus and epitrochlearis (Epi) muscles. However, much higher activation of these kinases in Epi muscles from young rats compared with soleus results in a greater effect of these kinases on insulin signaling in fast-twitch muscle with age. Heat shock protein (HSP) 72 expression and phosphorylation of HSP25 were higher in soleus compared with Epi muscles, and both parameters decreased with age. Age and fiber type differences in cytochrome oxidase activity are consistent with observed changes in HSP expression and activation. Our results demonstrate a significant difference in the ability of slow-twitch and fast-twitch muscles to respond to insulin and regulate glucose with age. A greater constitutive HSP expression and lower stress kinase activation may account for the ability of slow-twitch muscles to preserve the capacity to respond to insulin and maintain glucose homeostasis with age.

Original languageEnglish (US)
Pages (from-to)839-848
Number of pages10
JournalJournal of applied physiology
Issue number3
StatePublished - Sep 2008


  • Glucose uptake
  • Heat shock protein 25
  • Heat shock protein 72
  • Insulin receptor substrate-1
  • Serine phosphorylation
  • Stress kinases

ASJC Scopus subject areas

  • Medicine(all)


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