Mechanistic Target of Rapamycin (Mtor) Is Essential for Murine Embryonic Heart Development and Growth

Abstract

Mechanistic target of rapamycin (Mtor) is required for embryonic inner cell mass proliferation during early development. However, Mtor expression levels are very low in the mouse heart during embryogenesis. To determine if Mtor plays a role during mouse cardiac development, cardiomyocyte specific Mtor deletion was achieved using α myosin heavy chain (α-MHC) driven Cre recombinase. Initial mosaic expression of Cre between embryonic day (E) 10.5 and E11.5 eliminated a subset of cardiomyocytes with high Cre activity by apoptosis and reduced overall cardiac proliferative capacity. The remaining cardiomyocytes proliferated and expanded normally. However loss of 50% of cardiomyocytes defined a threshold that impairs the ability of the embryonic heart to sustain the embryo’s circulatory requirements. As a result 92% of embryos with cardiomyocyte Mtor deficiency died by the end of gestation. Thus Mtor is required for survival and proliferation of cardiomyocytes in the developing heart.

Loss of long‐chain acyl‐CoA synthetase isoform 1 impairs cardiac autophagy and mitochondrial structure through mechanistic target of rapamycin complex 1 activation

“…Compared with controls, the oxidation of [2][3][4][5][6][7][8][9][10][11][12][13][14] C]pyruvate was 2-fold higher in Acsl1 T2/2 cardiac mitochondria, consistent with increased flux through the tricarboxylic acid cycle (Fig. 1H).…”

“…In the heart, mTORC1 activation is required for growth; both global and cardiac-specific knockouts of mTOR are embryonic lethal (14,48). A temporal knockout of mTOR in adult heart demonstrated that mTOR is also needed for normal mitochondrial function, fatty acid oxidation, and heart contraction (16).…”

“…To quantify fatty acid uptake, 1.5 mCi 2-Br- [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]palmitate complexed to bovine serum albumin was injected retro-orbitally.…”

“…1C), suggesting that any compensation by other ACSL isoforms had done little to increase ACSL activity. We measured mitochondrial oxidation of [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]palmitate to both CO 2 and acid soluble metabolites, which are measures of complete and incomplete oxidation, respectively. The diminished activation of fatty acids to acyl-CoAs resulted in 94% lower [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]palmitate oxidation than in control cardiac mitochondria (Fig.…”

“…Within 10 wk of inducing the knockout, hearts lacking ACSL1 develop mTORC1-dependent hypertrophy (12). mTORC1 activation has many consequences in cells, including stimulation of growth and protein synthesis (13,14), regulation of lipid metabolism (15,16), and inhibition of autophagy (17). Inhibition of mechanistic target of rapamycin (mTOR) is associated with longer life span (18), but total loss of mTOR in the heart inhibits mitochondrial respiratory function and causes heart failure (16).…”