TY - JOUR
T1 - Age-related differences in skeletal muscle insulin signaling
T2 - The role of stress kinases and heat shock proteins
AU - Gupte, Anisha A.
AU - Bomhoff, Gregory L.
AU - Geiger, Paige C.
PY - 2008/9
Y1 - 2008/9
N2 - 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.
AB - 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.
KW - Glucose uptake
KW - Heat shock protein 25
KW - Heat shock protein 72
KW - Insulin receptor substrate-1
KW - Serine phosphorylation
KW - Stress kinases
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U2 - 10.1152/japplphysiol.00148.2008
DO - 10.1152/japplphysiol.00148.2008
M3 - Article
C2 - 18599680
AN - SCOPUS:53049104850
SN - 8750-7587
VL - 105
SP - 839
EP - 848
JO - Journal of applied physiology
JF - Journal of applied physiology
IS - 3
ER -