Introduction: Exposure to gestational obesity increases cardiometabolic disease risk in both human longitudinal cohorts and animal models. Male mice born to obese dams display cardiac hypertrophy and declining systolic and diastolic function. Despite alterations in cardiac mitochondrial respiratory function and ultrastructure in the offspring of obese dams, the role of mitochondrial metabolic changes in the programming of cardiac dysfunction by maternal obesity remains poorly defined.
Objective: To evaluate myocardial mitochondrial respiratory capacity in a well-established murine model of maternal obesity, we subjected banked cardiac tissue from 8wk-old offspring of both sexes to a protocol optimised for respirometry in frozen samples to profile electron transport chain (ETC) capacities.
Methods: Animal work was conducted in accordance with the UK Home Office Animal (Scientific Procedures) Act 1986 and following local ethical approval. Cardiac tissue was previously collected from 8wk-old C57BL/6J offspring mice of both sexes born to dams fed either a control (CC group) or obesogenic diet (OC group) for 10 weeks prior to mating and throughout gestation. Frozen cardiac tissue was homogenised in MiR06 respiration medium and transferred to Oxygraph-O2K chambers. A substrate inhibitor titration was initiated to determine uncoupled capacities of ETC complex I (CI; NADH), complexes I+II (maximal ETC capacity; NADH + succinate), complex II (CII; succinate + rotenone), and complex IV (CIV; TMPD + ascorbate). Respiratory oxygen fluxes (JO2) were normalised to chamber homogenate dry weight and maximal ETC capacity, and analysed by two-way ANOVA for sex and maternal diet (n = 7).
Results: Uncoupled respiratory complex activities normalised to tissue weight did not significantly differ between the 2 offspring groups, suggesting no overt changes in mass-specific mitochondrial respiratory capacity, although the CI-linked JO2/maximal ETC capacity ratio was higher in the OC group (control: 0.37 vs. obese: 0.41, P = 0.041). Mass-specific CI-linked ETC activity (male: 171.97 pmol O2/[s×mg dw] vs. female: 117.29 pmol O2/[s×mg dw], P = 0.077) and CI/maximal ETC capacity ratio (male: 0.42 vs. female: 0.37, P = 0.0065) were higher in male offspring, with females exhibiting a trend towards lower CII activity normalised to maximal ETC (male: 0.69 vs. female: 0.73, P = 0.054).
Conclusion and further work: Despite no differences in mass-specific uncoupled respiratory complex activities, suggesting an overall preservation of cardiac mitochondrial respiratory capacity, CI activity as a proportion of maximal ETC capacity was increased in maternal obesity exposed offspring, potentially indicating an early remodelling of relative respiratory complex activities. Further work is necessary to profile the stoichiometry of respiratory complex expression, and to define the wider mitochondrial metabolic phenotype in these samples.