Maternal Obesity Programs Offspring Muscle Mitochondrial Function

Abstract

A high-fat (HF) diet induces metabolic disease while initially increasing muscle mitochondrial content: a putative compensatory response to increased reactive oxygen species (ROS). Maternal obesity exacerbates the metabolic syndrome phenotype in offspring weaned to a HF diet, but little is known about the effects of maternal obesity on muscle mitochondrial function. PURPOSE: To determine whether maternal obesity influences muscle mitochondrial function in offspring weaned to a HF diet. METHODS: Female mice were fed a control (CON, 10% kcal) or HF (45% kcal) diet to induce maternal obesity prior to mating. Diets were maintained throughout pregnancy and lactation. Male offspring (n=30) were weaned to HF or CON diet creating 4 groups (CON/CON, CON/HF, HF/CON, HF/HF). At 12 months body composition (DEXA) and mitochondrial function in permeabilized gastrocnemius bundles (high-resolution respirometry) was determined. RESULTS: Newborns and adult offspring of obese dams were heavier than CON. Percent lean body mass was lower in offspring of obese mice, and those weaned to a HF diet (71±2, 52±2, 60±2, 50±1 % in the 4 groups respectively; effect of maternal obesity and HF diet p<0.05, two-way ANOVA). Maximal muscle fatty-acid (palmitoyl+carnitine, PC) and carbohydrate (glutamate) driven respiration with saturating ADP, oxidative phosphorylation (OXPHOS) and electron transport system capacity (ETS) were each greater in HF diet (p<0.05). Flux control ratio for ADP+PC was also greater in HF diet (0.15±0.05, 0.25±0.06, 0.16±0.04, 0.23±0.05, p<0.05). OXPHOS capacity tended to be lower in offspring of obese dams (64±16, 82±21 vs. 56±16, 72±12 pmol/s/mg, effect of maternal obesity p=0.2) and was accompanied by a greater LEAK respiration (5.7±3.1, 7.5±2.1 vs. 8.0±2.3, 8.7±3.8 pmol/s/mg, effect of maternal obesity p=0.06). CONCLUSIONS: Greater LEAK in offspring of obese dams indicates pathologically dyscoupled respiration, perhaps consequent to increased ROS. Despite this, muscle oxidative capacity tended to be lower in the muscles of offspring of obese dams. Maternal obesity may contribute to HF-diet associated metabolic disease by ameliorating the compensatory increase in muscle mitochondrial content and function. Support: March of Dimes 030344; Pulmonary Education and Research Foundation.