Impaired Satellite Cell Differentiation Capacity and Myotube Insulin Responsiveness in Lambs with Intrauterine Growth Restriction

Abstract

Establishing adequate muscle mass is essential for metabolic health. Fetuses with intrauterine growth restriction (IUGR) are born with less muscle mass than appropriate for gestational age infants and never fully recover, as those born IUGR demonstrate persistent reductions in lean body mass in adulthood. Consequently, children and adults with IUGR have an increased risk of developing type 2 diabetes, obesity, and other complications associated with the metabolic syndrome. In order to better understand the in utero programming paradigm of IUGR on skeletal muscle growth and metabolism, we isolated satellite cells from one-month-old lambs and examined their function because of their role in muscle growth. In this series of experiments, we establish a differentiation protocol and show that satellite cells grown on Matrigel (P ≤ 0.05) and in the presence of a TGFβ inhibitor (P ≤ 0.05) have increased fusion events after 3 - 4 days of differentiation. Importantly we found that differentiation of IUGR satellite cells, measured by percent fusion, was greater than controls (P ≤ 0.05). However this difference was lost when cultures were exposed to a TGFβ inhibitor for 24 hours (P > 0.05). Using our optimized differentiation protocol to produce myotubes, we measured insulin-stimulated glucose uptake. IUGR myotubes were less responsive to insulin compared to controls (P < 0.01). These findings demonstrate for the first time that satellite cells from IUGR lambs exhibit disturbed glucose metabolism and differentiation capacity, which indicates that satellite cells become programmed by conditions associated with IUGR.