Abstract 12871: Maternal Obesity is Sufficient to Induce Transgenerational Cardiac Mitochondrial Dysfunction in Mice

• Published in: Circulation (New York, N.Y.) N.Y.), 2018-11, Vol.138 (Suppl_1 Suppl 1), p.A12871-A12871
• Main Authors: Ferey, Jeremie L, Kovacs, Attila, Diwan, Abhinav, Moley, Kelle H
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539

IntroductionMaternal obesity is correlated with increased risk of cardiovascular disease in the offspring in humans. We have observed impaired mitophagy in oocytes of obese mouse dams. Whether the observed mitochondrial abnormalities result in cardiac pathology in the offspring is unknown.HypothesisMaternal obesity induces cardiac pathology through transgenerational inheritance of mitochondrial dysfunction.MethodsC57Bl6 female mice (F0) fed chow or a high-fat/high-sucrose (HFS) diet were mated with chow-fed males to generate F1 mice. F1 females from chow-fed and HFS-fed dams were mated with chow-fed males to generate F2 and F3 mice. F1 males were similarly mated to generate a paternal lineage F2 (PF2) to determine if the phenotype was restricted to maternal mitochondrial transmission. Oocytes from chow-fed or HFS-fed F0 mice were fertilized in vitro and transferred to pseudo-pregnant chow-fed ICR mice to generate embryo transfer (ET) offspring to exclude a role of in-utero environment and lactation. Cardiac structure and function was evaluated by echocardiography; and transmission electron microscopy and high-resolution respirometry were employed to assess cardiac mitochondrial structure and function.ResultsF1 and F2 offspring of both sexes from HFS-fed dams developed cardiac hypertrophy (~7-10% increase in ratio of heart weight/tibial length and left ventricular (LV) mass to body weight vs. chow-fed) with reduced LV% endocardial fractional shortening in F1, despite being chow-fed and non-obese. LV hypertrophy was also observed in PF2 and ET offspring of both sexes from HFS-fed dams. Cardiac mitochondria demonstrated structural abnormalities with cristal rarefaction and reduced oxygen consumption (by ~30-50%) in F1-F3, PF2 and ET offspring from HFS-fed dams vs. chow-fed controls. Similar mitochondrial defects were evident in the F3 generation (~30%) indicating transgenerational inheritance.ConclusionCardiac mitochondrial abnormalities are transgenerationally inherited through offspring of either sex from obese mothers to induce cardiac hypertrophy. Understanding obesity-induced epigenome alterations in oocytes could enable development of therapies to target inheritance of heart disease risk in humans.