Local IGF‐I enhances the sensitivity of muscle protein synthesis to insulin

Abstract

Skeletal muscle protein synthesis in the immature muscle is highly sensitive to insulin and nutrients. We hypothesized that this sensitivity of protein synthesis to insulin is attributable to local IGFs that are expressed at a significant level by immature skeletal muscle. To test the hypothesis, transgenic mice with high muscle IGF-I (SIS2, n=68) and wildtype (Wt, n=71) controls at 3, 5, and 10 wk were assigned to one of three treatments (fasted; refed; refed+diazoxide (to block insulin secretion)). After an overnight fast, mice were refed for 90 min. Skeletal muscle fractional protein synthesis rate (FSR) was measured in vivo over the last 15 min using a flooding dose of 3[H]-phenylalanine (1.5 mmol phe/kg BW). Blood was collected to measure serum insulin and glucose. The feeding-induced increase in insulin (P < 0.01) was blocked by diazoxide treatment and insulin remained at or fell below fasting levels. Glucose levels in the refed group were similar to fasting levels, but increased 2- to 4-fold (P < 0.01) in diazoxide-treated mice. Fasted SIS2 mice had higher FSR compared to fasted Wt mice at all ages (P < 0.05). Refeeding increased FSR for both genotypes at all ages (P < 0.01). Diazoxide treatment inhibited the feeding-induced stimulation of FSR: in Wt mice FSR remained at fasting levels, whereas in SIS2 mice FSR decreased (P < 0.01) to values similar to those of Wt fasted mice. The higher FSR in fasted SIS2 mice is consistent with the hypothesis that local IGF enhances the sensitivity of muscle protein synthesis to insulin. Upon refeeding insulin contributed more than nutrients to the increase in muscle FSR. (Funded in part by NIAMS; AR-46308, MF; AR51684, WO)