Maternal Western‐style diet and obesity during pregnancy reduces mitochondrial Complex I‐linked oxidative capacity in tandem with decreased oxidative stress in skeletal muscle of adolescent Japanese macaque offspring

Abstract

BackgroundExposure to an obesogenic gestational environment during early development increases offspring risk of developing obesity and cardiometabolic diseases. Skeletal muscle of obese and insulin resistant individuals show signs of mitochondrial dysfunction including reduced oxidative capacity and increased oxidative stress. Subsequent oxidative damage is caused by reactive oxygen species (ROS) generated primarily by mitochondrial Complex I (CI). Previous work in our non‐human primate model shows decreased oxidative capacity in fetal skeletal muscle from obesogenic pregnancies, a phenotype we have confirmed is retained into adolescence. The purpose of this study was to evaluate how this reduced oxidative capacity correspond with ROS production in skeletal muscle of lean adolescent offspring.Experimental DesignLean (body fat <25%) adult female Japanese macaques were maintained on a control diet (CD) or Western‐style diet (WD) prior to and throughout pregnancy and lactation. Dams chronically consuming WD with body fat >30% were classified as obese and included in this study. Male and female offspring were weaned to CD and moved to independent housing at 7 months of age. Muscle samples were collected from offspring gastrocnemius (gastroc) and soleus at 40 months. Offspring data were analyzed by Student’s t‐test.ResultsExposure to maternal WD during pregnancy showed moderate but significant reductions in oxidative damage and a modest (but insignificant) decrease in ROS generation in gastroc of offspring from obese pregnancies. In the soleus, ROS production was significantly reduced in these offspring. Both nuclear‐ and mitochondrial‐encoded genes for CI were decreased with maternal obesity/WD pregnancy, indicating transcriptional regulation of CI in exposed offspring. Finally, CI protein abundance was also decreased in primary myotubes from these offspring in lieu of additional metabolic challenges, providing further evidence of lasting metabolic reprogramming in skeletal muscle.ConclusionsWe find that early life exposure to maternal WD‐induced obesity leaves a lasting impression on offspring skeletal muscle metabolism that persists into young adulthood. It is possible that transcriptional suppression of CI activity is a protective adaptation to mitigate oxidative damage caused by mitochondrial ROS. While long‐term consequences of altered oxidation patterns relating to ROS flux require further investigation, the loss of CI content and diminished oxidative capacity in these lean offspring likely drive their increased susceptibility for cardiometabolic diseases – particularly when faced with metabolic stress and environmental insults throughout the lifespan.