Adaptations of skeletal muscle insulin signaling following hindlimb suspension
AuthorO'Keefe, Matthew Phillip
KeywordsBiology, Animal Physiology.
AdvisorHenriksen, Erik J.
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractHindlimb suspension (HS) in rats was used to study the effects of simulated microgravity on whole-body glucose tolerance and soleus muscle insulin signaling. Following short-term HS (1-day), glucose intolerance and whole-body insulin resistance developed. Insulin resistance was also identified at the skeletal muscle level, with the type I soleus showing more insulin resistance than the type II extensor digitorum longus (EDL). Examination of insulin signaling components in the soleus revealed a tendency towards a decrease in the expression of the p85 regulatory subunit of phosphatidylinositol-3 kinase (PI3-K) in addition to a decrease in the basal phosphorylation levels of Akt. These changes may contribute to the observed insulin resistance in the soleus, but clearly other factors likely also contribute. The data from the whole-body and muscle studies after 1-day HS did not clearly identify the factors responsible for the observed glucose intolerance and reduced glucose uptake. However, because both the soleus and EDL exhibited decreased insulin-mediated glucose uptake, there may be a circulating factor responsible for the observed insulin resistance and glucose intolerance. The whole-body glucose intolerance and muscle insulin resistance was no longer apparent after 3-day HS. Interestingly, 7-day HS resulted in the development of enhanced whole-body insulin sensitivity. In both 3-day and 7-day HS soleus, insulin action on glucose transport was increased. In addition, GLUT-4 protein and activities of hexokinase and citrate synthase were increased with prolonged HS. Following 3-day HS, expression of insulin receptor substrate-1 (IRS-1) and -2 (IRS-2) were decreased. However, assessment of the functionality of signaling proteins indicated insulin-induced increases in tyrosine phosphorylation per unit IRS-1 protein, IRS-1 association with p85, and Akt phosphorylation. The PI3-kinase inhibitor wortmannin did not completely block the observed increases in insulin-mediated glucose transport in 3-day and 7-day HS soleus, indicating the small role of a P13-K independent mechanism. These results indicate that prolonged HS (3-7 days) can alter the functionality of specific insulin signaling components in the soleus muscle, accounting for most of the increase in insulin-stimulated glucose uptake induced by simulated weightlessness.
Degree ProgramGraduate College