Maternal obesity impairs fetal cardiomyocyte contractile function in sheep

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 ofMOon fetal cardiomyocyte contractility at term. We observedthatMOimpaired cardiomyocyte contractilityby reducing peak shortening andshortening/relengthening velocity, prolonging time to relengthening. MO disrupted Ca²⁺ homeostasis in fetal cardiomyocytes, increasing intracellular Ca²⁺ and inducing cellular Ca²⁺ insensitivity. The Ca²⁺-release channelwas impaired, but Ca²⁺ uptake was unaffected byMO. The upstreamkinases 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)-b to MHC-a 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 aberrantmyofilament protein composition. Thesemechanisms may contribute to developmental programming by MOof offspring cardiac function and predisposition to later life cardiovascular disease in the offspring.