Peripartum stress impairs cardiac function in female mice lacking myosin-5b in cardiomyocytes

Peripartum cardiomyopathy (PPCM) is characterized by maternal systolic heart failure (HF) due to left ventricular (LV) dysfunction in heart-healthy women with peripartum onset.

Unconventional class-5 myosin motor myosin-5b is involved in the transport of mRNA/ribosome complexes important for sarcomere function, Ca2+ homeostasis, cardiac conductance and energy uptake.

Here, we investigated the regulation and role of myosin-5b during pregnancy and postpartum in the maternal heart.

Peripartum stress was associated with increased cardiac Myo5b expression in WT mice after 2 consecutive pregnancies and nursing periods compared with age-matched nulli-pari (NP) mice. In contrast, mice with PPCM due to cardiac STAT3 deficiency revealed a decreased Myo5b mRNA expression compared with WT postpartum (PP) mice. The role of cardiac myosin-5b in the peripartum phase was analyzed in mice with a cardiomyocyte-specific knockout (KO) of Myo5b (KO: aMHC-Cre;Myo5bflox/flox; WT: Myo5bflox/flox). KO females developed normally up to the age of 3 months (M) (LV function FS%: WT: 36±12, KO: 35±7), but showed a reduced cardiac function in an age of 6M (FS%: WT 31±11, KO 22±10, p<0.05) associated with premature mortality. After exposing KO mice to pregnancy and nursing, echocardiographic analysis revealed a decrease in LV function in KO PP mice compared with age-matched KO NP mice, already after the first nursing period (FS%: KO NP: 33±6, KO PP: 23±7, P<0.01), which continued to decrease after the second nursing period (FS%: KO NP: 22±10, KO PP: 9±4, P<0.01). The mortality increased relative to the number of pregnancies and advancing age, compared with age-matched KO NP females. Molecular and morphologic analysis after 2-3 consecutive pregnancy and nursing periods revealed that KO PP mice developed enhanced cardiac hypertrophy characterized by increased heart weight, cardiomyocyte cross-sectional area and an elevated mRNA expression of the hypertrophic and HF markers Anp, Bnp and Ankrd1. Moreover, KO PP mice displayed increased cardiac fibrosis and inflammation. The PPCM related markers PAI-1 and miR-146a were increased and the cardioprotective ErbB4 signalling is reduced in LV tissue of KO PP compared with KO NP. RNA-Seq analysis of KO 1PP LVs revealed 241 transcripts (adj. P<0.01) differently regulated compared with KO NP mice. Moreover, GLUT4 mRNA and protein expression were reduced in LV tissue of KO PP compared to KO NP. Further analyses in isolated adult cardiomyocytes revealed that MYO5b is involved in baseline and insulin induced cardiac glucose uptake and is associated to mitochondrial proteins.

Myo5b expression is upregulated late in pregnancy and postpartum suggesting a potential role in the compensation of peripartum stress in the maternal heart. Cardiomyocyte myosin-5b deficiency promotes HF in the peripartum phase. First data suggest that myosin-5b is involved in the cardiac metabolism.