Effect of maternal diet and body condition on glucose metabolism and skeletal muscle structure in mature adult sheep offspring

Early life nutrition is implicated in the risk of metabolic diseases (e.g. type 2 diabetes) in adulthood. Low birth-weight was associated with defects in the skeletal muscle insulin-signalling pathway of young adult men (1), and insulin resistance was associated with changes in myofibre composition (2). In sheep, maternal undernutrition reduced fetal skeletal muscle myofibre density and composition (3). Recently we reported that lower body condition score (BCS) led to increased fasting glycaemia, mild glucose intolerance and impaired initial insulin secretory response in adult offspring (4). We hypothesised that this would worsen with age, and that altered skeletal muscle structure and insulin signalling pathways are involved. Ewes were established, by dietary manipulation, at a BCS of 2 (lower (L) n = 10) or >3 (higher (H) n = 14) before and during pregnancy (4). In male offspring at 4.04±0.02 years plasma glucose and insulin concentrations were measured during a glucose tolerance test (0.5 g/kg body weight i.v.) and rams were killed by an overdose of barbiturate (i.v. 145 mg/kg). We analysed a) insulin-signalling proteins by Western blotting in abdominal fat and vastus muscle (m.); b) glucose uptake in isolated strips of vastus and soleus m.(5); c) myofibre density and cross-sectional area (CSA) by immunostaining with anti-fast skeletal myosin (3). Data are mean±SE and were analysed by Student’s t test. Glucose tolerance was similar between groups. Basal glucose uptake was similar in L and H group soleus and vastus m. isolated strips. However insulin-stimulated uptake tended to be reduced in the soleus m. only of L rams (H 1.01±0.06; L 0.84±0.07 pmol.min.mg, p<0.1). In vastus, but not soleus, m. total myofibre density (H 343±15; L 294±14 fibres/mm2, p<0.05) and fast myofibre density (H 226±10; L 194±10 fibres/mm2, p<0.05) was lower in L rams. Slow myofibre density tended to be lower in L rams (H 117±7; L 100±6 fibres/mm2, p<0.1). Myofibre CSA was unaltered. Protein levels of (i) Akt1 were lower in the vastus m. (L=83±7% of H, p<0.05), and tended to be lower in abdominal fat (L=71±7% of H, p<0.1), of L rams; (ii) GLUT-4 were increased (L=157±6% of H, p<0.001), and (iii) IGF-IR tended to be reduced (L=78±12% of H, p<0.1), in the vastus m. of L rams. Reduced signalling through Akt1 may therefore mediate the decreased vastus m. myofibre density in L rams resulting in reduced glucose tolerance of the young adult offspring (4). However in mature adulthood, glucose tolerance and glucose uptake into vastus m. was not altered by maternal BCS, and thus the impact of reduced myofibre density may be offset in part by increased GLUT-4. Such adaptations may lead to complications in metabolic control in an overabundant postnatal nutrient environment