Maternal obesity impairs fetal cardiomyocyte contractile function in sheep

Abstract

Obesity is a major public health problem worldwide. In the United States, one‐third of women of reproductive age are obese. Human studies show that maternal obesity (MO) predisposes offspring to cardiovascular disease. However, the underlying mechanisms remain unclear. Given the similarities between pregnancy in sheep and humans, we studied sheep to examine the impact of MO on fetal cardiomyocyte contractility at term. We observed that MO impaired cardiomyocyte contractility by reducing peak shortening and shortening/relengthening velocity, prolonging time to relengthening. MO disrupted Ca2+ homeostasis in fetal cardiomyocytes, increasing intracellular Ca2+ and inducing cellular Ca2+ insensitivity. The Ca2+‐release channel was impaired, but Ca2+ uptake was unaffected by MO. The upstream kinases that phosphorylate the Ca2+‐release channel — ryanodine receptor‐2, PKA, and calmodulin‐dependent protein kinase II—were activated in MO fetuses. Contractile dysfunction was associated with an increased ratio of myosin heavy chain (MHC)‐β to MHC‐α and upregulated cardiac troponin (cTn)‐T and tropomyosin, as well as cTn‐I phosphorylation. In summary, this is the first characterization of the effects of MO on fetal cardiomyocyte contractility. Our findings indicate that MO impairs fetal cardiomyocyte contractility through altered intracellular Ca2+ handling, overloading fetal cardiomyocyte intracellular Ca2+ and aberrant myofilament protein composition. These mechanisms may contribute to developmental programming by MO of offspring cardiac function and predisposition to later life cardiovascular disease in the offspring.—Wang, Q., Zhu, C., Sun, M., Maimaiti, R., Ford, S. P., Nathanielsz, P. W., Ren, J., Guo, W. Maternal obesity impairs fetal cardiomyocyte contractile function in sheep. FASEB J. 33, 2587–2598 (2019). http://www.fasebj.org

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The ryanodine receptor stabilizer S107 ameliorates contractility of adult Rbm20 knockout rat cardiomyocytes

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