Description:
<jats:p>Mechanistic target of rapamycin (mTOR) kinase operates in two functionally and structurally distinct multiprotein complexes mTORC1 and mTORC2. mTORC1 including its defining raptor protein is a critical mediator of myocardial growth. We induced cardiomyocyte specific raptor-KO (cKO) deletion to investigate a sex specific role of mTORC1 during cardiac adaptation in normotensive DOCA-salt mice. Untypical for this mild cardiac stress model, raptor-cKO females had sharper decrease in EF (51 vs. 26%) than males (50 vs. 32%) already at 3 weeks after start of DOCA-salt challenge. Male raptor-cKO mice mounted eccentric hypertrophic response upon DOCA-salt indicated by heart weight/tibia length ratios (6.7 to 8.0) as compared to their WT litters (6.6 to 7.6). In contrast female raptor-cKO (5.8 to 6.4) minimally differed from their litters (5.8 to 6.6). Severe dilative phenotype was detected in both sexes regardless of DOCA-salt challenge. In addition, we found tremendous diffuse left ventricular fibrosis which was also more prominent in raptor-cKO females. Collagen depositions in the LV visualized by Sirius red staining increased 10fold in males (1.0 to 10.6%) and 15fold in females (0.9 to 15.7%), respectively. Expression of raptor protein in the heart was diminished by 80% in raptor cKO mice of both sexes what lead to similar extent of decreased activity of direct mTORC1 downstream targets phospho-S6 ribosomal protein and phospho-4E-BP1Ser65 (68% reduction in males vs. 61% in females. Over-compensatory mTORC2 activation in cKO animals via phospho-AKTSer473 (12fold increase) and induction of anti-apoptotic signaling was similar in both sexes. However, raptor-cKO females failed to up-regulate expression of mitochondrial genes such as Mtnd1 (ND1), mt-Co1 (COX1) and Atp5i (ATP5k), stressing sex differences in mTORC1 dependent mitochondrial adaptation. In addition, transmission electron microscopy (TEM) points towards structural alterations of mitochondrial morphology.</jats:p>
<jats:p>Intact mTORC1 function is important for myocardial adaptation in both sexes. More severe phenotype in females further implicates mTORC1 to be essential for intrinsic female cardio protection.</jats:p>