Calorie restriction leads to greater Akt2 activity and glucose uptake by insulin-stimulated skeletal muscle from old rats.

Skeletal muscle insulin resistance is associated with many common age-related diseases, but moderate calorie restriction (CR) can substantially elevate glucose uptake by insulin-stimulated skeletal muscle from both young and old rats. The current study evaluated the isolated epitrochlearis muscle from ~24.5-mo-old rats that were either fed ad libitum (AL) or subjected to CR (consuming ~65% of ad libitum, AL, intake beginning at ~22.5 mo old). Some muscles were also incubated with MK-2206, a potent and selective Akt inhibitor. The most important results were that in isolated muscles, CR vs. AL resulted in 1) greater insulinstimulated glucose uptake 2) that was accompanied by significantly increased insulin-mediated activation of Akt2, as indicated by greater phosphorylation on both Thr³⁰⁹ and Ser⁴⁷⁴ along with greater Akt2 activity, 3) concomitant with enhanced phosphorylation of several Akt substrates, including an Akt substrate of 160 kDa on Thr⁶⁴² and Ser⁵⁸⁸, filamin C on Ser²²¹³ and proline-rich Akt substrate of 40 kDa on Thr²⁴⁶, but not TBC1D1 on Thr⁵⁹⁶; and 4) each of the CR effects was eliminated by MK-2206. These data provide compelling new evidence linking greater Akt2 activation to the CR-induced elevation of insulin-stimulated glucose uptake by muscle from old animals. [ABSTRACT FROM AUTHOR]