Moderate nutrient restriction dysregulates molecular markers of calcium handling in the left ventricle of the non‐human primate fetal heart

Maternal nutrient restriction (MNR) increases cardiovascular disease (CVD) in offspring. In baboon offspring of moderate MNR, left ventricle (LV) function resembles a premature ageing and heart failure phenotype in young adulthood. The underlying cellular mechanisms responsible for this high-risk cardiac phenotype in MNR offspring are unknown. We hypothesized that calcium (Ca²⁺) dysfunction originates in utero and is programmed to persist after birth. We studied a baboon model of moderate MNR to investigate the impacts on molecular markers of Ca²⁺ handling that regulate contractility. Beginning at ∼30 days gestational age (dGA) female baboons (Papio hamadryas spp.) of similar age and weight were randomly assigned to either control or MNR diets (70% of the control diet). At 165 dGA (term, 184 dGA) we assessed markers of Ca²⁺ handling in the fetal LV. Alterations were observed in both sexes, including increased adrenoreceptor beta 2 (ADRB2) expression and protein abundance of phosphorylated phospholamban (p-PLN) and calmodulin-dependent kinase II (p-CAMKII) in MNR compared to control fetuses. However dysregulated Ca²⁺ handling may have sex-specific effects, with calsequestrin (CSQ; involved in Ca²⁺ buffering in the sarcoplasmic reticulum) decreased in only MNR male fetuses compared to control males. Fetal cardiac tissue concentrations of the thyroid hormone thyroxine were reduced in MNR males compared to control males. This study sheds light on sex-specific CVD risk and supports the hypothesis that the mechanisms contributing to cardiac dysfunction in MNR-born young adults may be Ca²⁺ mishandling originating in utero. A greater understanding of CVD aetiology will improve the identification and treatment of at-risk individuals. KEY POINTS: Moderate maternal nutrient restriction (MNR; 70% of control diet) throughout pregnancy leads to biventricular dysfunction resembling premature ageing in young adult non-human primates. We investigated whether this high-risk phenotype in offspring originates in utero due to alterations in the hormonal and contractility profile in the fetal left ventricle (LV). MNR decreased cardiac tissue thyroid hormone thyroxine (T4) concentrations in the LV of males by ∼22% and increased type 3 iodothyronine deiodinase (DIO3) mRNA expression in both sexes. MNR increased the gene expression of adrenoreceptor beta 2 (ADRB2) and the phosphorylation of phospholamban (p-PLN) and calmodulin-dependent kinase II (p-CAMKII) in both sexes. MNR decreased the abundance of calsequestrin (CSQ2) in the LV of males only. Early origins of Ca²⁺ mishandling, including sex-specific changes, may contribute to high-risk cardiac phenotypes in MNR offspring in later life.