Postnatal Growth Restriction In Mice Alters Cardiac Mitochondrial Energetics

Abstract

Postnatal growth-restriction (PGR) is associated with increased risk of cardiovascular mortality. We hypothesize that nutrient restriction alters metabolism leading to cardiac failure. PURPOSE: To determine the effect of PGR on mitochondrial respiratory capacity (JO2). METHODS: FVB mouse dams were fed a control(CON: 20% protein), or a low-protein(LP: 8% protein) isocaloric diet 2-weeks before mating. LP-dams produce 18% less milk and pups nursed by LP-dams undergo growth restriction. At postnatal day (PN) 1, pups born to dams fed the CON diet were crossed to LP-dams(PUN; postnatally undernourished) or a different CON-dam. At PN21, all mice were weaned to the CON-diet. On PN22 or PN80, mice were weighed, euthanized, and hearts removed. Hearts were weighed and cardiac mitochondria were isolated via differential centrifugation. Respiration was measured through high-resolution respirometry in the presence of 5 mM pyruvate and 1 mM L-malate(PM). Two-way ANOVAs were performed with the main effects of diet (CON vs. PUN) and age(PN22 vs. PN80) to compare, body-mass, heart-mass, and JO2. An α level of 0.05 was set a priori, and if necessary, a Tukey’s HSD post hoc test was used for multiple comparisons. RESULTS: PGR caused significant diet and age effects (p<.001) on final body-mass between CON (PN22: 12.01±0.83g; PN80: 23.51±2.95g) and PUN groups (PN22: 8.45±0.61g; PN80: 21.32±3.42g). Heart-mass was also significantly reduced (p<.001) in PUN (PN22: 0.06±0.01g; PN80: 0.11±0.012g) compared to CON (PN22: 0.08±0.007g; PN80: 0.12±0.01g) across the lifespan. LEAK state JO2 was significantly higher (p<.001) at both time-points in PUN (PN22: 46.48±4.25nmol/mg/min, PN80: 48.74±8.34nmol/mg/min) compared to CON (PN22: 36.15±5.60nmol/mg/min, PN80: 38.23±2.74nmol/mg/min). The respiratory control ratio (RCR) was significantly reduced (p=0.0005) in PUN (PN22: 7.81±0.48, PN80: 7.32±1.48) compared to CON (PN22: 9.25±0.73, PN80: 9.14±0.74). CONCLUSIONS: PGR decreased body and heart-mass across the life span and increased LEAK state JO2 in the presence of PM, indicating mitochondrial impairment at PN22 and PN80. PGR caused reductions in RCR, which may cause CVD, thus PGR increases CVD risk through uncoupling of mitochondria. Exercise may improve mitochondrial function in PGR mouse hearts.