Postnatal undernutrition alters adult female mouse cardiac structure and function leading to limited exercise capacity

Abstract

Key points Impaired growth during fetal life can reprogramme heart development and increase the risk for long‐term cardiovascular dysfunction. It is uncertain if the developmental window during which the heart is vulnerable to reprogramming as a result of inadequate nutrition extends into the postnatal period. We found that adult female mice that had been undernourished only from birth to 3 weeks of age had disproportionately smaller hearts compared to males, with thinner ventricle walls and more mononucleated cardiomyocytes. In females, but not males, cardiac diastolic function, and heart rate responsiveness to adrenergic stimulation were limited and maximal exercise capacity was compromised. These data suggest that the developmental window during which the heart is vulnerable to reprogramming by inadequacies in nutrient intake may extend into postnatal life and such individuals could be at increased risk for a cardiac event as a result of strenuous exercise. Abstract Adults who experienced undernutrition during critical windows of development are at increased risk for cardiovascular disease. The contribution of cardiac function to this increased disease risk is uncertain. We evaluated the effect of a short episode of postnatal undernutrition on cardiovascular function in mice at the whole animal, organ, and cellular levels. Pups born to control mouse dams were suckled from birth to postnatal day (PN) 21 on dams fed either a control (20% protein) or a low protein (8% protein) isocaloric diet. After PN21 offspring were fed the same control diet until adulthood. At PN70 V̇O2, max was measured by treadmill test. At PN80 cardiac function was evaluated by echocardiography and Doppler analysis at rest and following β‐adrenergic stimulation. Isolated cardiomyocyte nucleation and Ca2+ transients (with and without β‐adrenergic stimulation) were measured at PN90. Female mice that were undernourished and then refed (PUN), unlike male mice, had disproportionately smaller hearts and their exercise capacity, cardiac diastolic function, and heart rate responsiveness to adrenergic stimulation were limited. A reduced left ventricular end diastolic volume, impaired early filling, and decreased stored energy at the beginning of diastole contributed to these impairments. Female PUN mice had more mononucleated cardiomyocytes; under resting conditions binucleated cells had a functional profile suggestive of increased basal adrenergic activation. Thus, a brief episode of early postnatal undernutrition in the mouse can produce persistent changes to cardiac structure and function that limit exercise/functional capacity and thereby increase the risk for the development of a wide variety of cardiovascular morbidities.

Postnatal Growth Restriction in Mice Alters Cardiac Protein Composition and Leads to Functional Impairment in Adulthood

“…Absolute heart mass of PGR mice was significantly less than controls at PN21, but not at PN80, suggesting heart mass was recuperated even though body mass was reduced ( Figure 2 ). These findings support previous growth restriction investigations [ 16 , 17 ], which demonstrate preferential organ development for the heart and brain. The “preferential sparing” of vital organs may come at the expense of peripheral structures, such as skeletal muscle and bone, leading to reduced body mass [ 3 ].…”

“…PGR impairs cardiomyocyte nucleation, leading to functional impairments in adulthood [ 17 ], therefore, a cell cycle regulator, p57 kip2 , was classified as a protein of interest based on existing literature and significant 2D DIGE results [ 15 , 17 , 21 , 22 , 23 , 24 ].…”

“…While there is extensive evidence on CV pathology due to intrauterine growth restriction [ 13 , 14 , 15 , 16 ], there is far less on the dysfunction caused by postnatal growth restriction (PGR). From the evidence available, PGR in a mouse impairs cardiac function due to a greater amount of mononucleated cardiomyocytes [ 7 , 17 ], impaired calcium flux [ 17 ], stiffer ventricles leading to diastolic dysfunction [ 7 ], and increased incidence of cardiac arrhythmias [ 12 ] when compared to non-growth restricted mice.…”

Dietary protein restriction throughout intrauterine and postnatal life results in potentially beneficial myocardial tissue remodeling in the adult mouse heart

“…Such diet regime results in maladaptive changes in the adult offspring heart, a pathological gene expression program and increased collagen deposition 41,42 . Dietary protein restriction initiated after birth and maintained throughout the lactation period or LPD started after weaning also negatively affect cardiomyocyte contractility and morphometry as well as myocardial fibrosis 43,44 . Our data show that constant pre- and postnatal LPD reduces cardiomyocyte size and myocardial fibrosis but increases capillary density in the adult heart compared to mice on SPD.…”

The Good, the Bad, and the Ugly of Pregnancy Nutrients and Developmental Programming of Adult Disease

“…Programming effects of protein restriction occur not only during pregnancy but also through breastfeeding. Mice offspring born to dams fed with low-protein diet during lactation have impaired cardiac structure and function that limit exercise/functional capacity [60].…”