Effect of IGF‐I and rapamycin on diaphragm muscle atrogenes with malnutrition

Abstract

We recently reported that the addition of rapamycin to IGF‐I decreased P‐Akt in the diaphragm (DIA) with acute nutritional deprivation (ND). As Akt impacts on pathways mediating proteolysis, the aim was to evaluate the influence of IGF‐I and rapamycin on rat DIA atrogenes with ND. Groups: 1) Controls (CTL); 2) ND (20% of food intake for 4 days); 3) ND+IGF‐I; and 4) ND+IGF‐I+rapamycin. DIA mRNA was analyzed by real‐time PCR. Foxo1 and 3a increased 2.3 and 2.9‐fold with ND, while Foxo4 decreased by 46%. IGF‐I reduced Foxo1 and 3a to CTL levels, while Foxo4 increased 2.5‐fold. Rapamycin negated all IGF‐I effects. ND increased MAFbx/Atrogin1 and MuRF1 by 2.7 and 19‐fold, with no change in E3‐[alpha]II. IGF‐I decreased these atrogenes to near CTL levels. Rapamycin returned these E3 ligases to ND levels. ND increased caspase 3 (important in myofibrillar disassembly) 4.8‐fold. IGF‐I decreased it to 1.5‐fold CTL. Rapamycin increased abundance to ND levels. ND increased myostatin (negative regulator of muscle mass) 2.4‐fold. IGF‐I reduced it to 0.78 CTL levels while rapamycin negated IGF‐I effects. We conclude that IGF‐I significantly reduces atrogenes and their regulators with ND. These positive effects were reversed with rapamycin, an mTOR inhibitor. We speculate that influences on mTOR feedback negatively on Akt and/or other regulators of pathways mediating protein degradation. Funded by NIH HL‐071227