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Akt signaling mediates postnatal heart growth in response to insulin and nutritional status
Ichiro Shiojima1, Mikkael Yefremashvili, Zhengyu Luo
1Molecular Cardiology/Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Insights
Akt signaling regulates heart growth based on nutrient availability. Enhancing Akt1 in mice with insulin receptor defects rescued small heart size, indicating its crucial role in physiological cardiac development.
Area of Science:
- Cardiovascular Biology
- Molecular Signaling
- Developmental Biology
Background:
- Akt is a key kinase regulating cellular responses.
- Akt signaling in the heart is linked to nutrient availability and cardiac growth during development.
Purpose of the Study:
- To investigate the role of Akt signaling in nutrient-dependent regulation of physiological heart growth.
- To elucidate the mechanism by which Akt mediates insulin-dependent cardiac development.
Main Methods:
- Studied Akt signaling and phosphorylation in mice with cardiac-specific insulin receptor deletion.
- Assessed the impact of caloric restriction on Akt phosphorylation in wild-type and mutant mice.
- Utilized forced expression of Akt1 to rescue cardiac phenotypes.
Main Results:
- Cardiac-specific insulin receptor deletion led to reduced Akt, S6K1, and 4E-BP1 phosphorylation and a small heart phenotype.
- Caloric restriction had minimal effect on Akt phosphorylation in mutant mice compared to wild-type.
- Forced Akt1 expression restored S6K1 and 4E-BP1 phosphorylation and rescued the small heart phenotype.
Conclusions:
- Akt signaling is essential for insulin-dependent physiological heart growth during postnatal development.
- Akt acts as a crucial mediator coordinating heart size with organismal nutritional status.
Abstract:
Akt is a serine-threonine kinase that mediates a variety of cellular responses to external stimuli. During postnatal development, Akt signaling in the heart was up-regulated when the heart was rapidly growing and was down-regulated by caloric restriction, suggesting a role of Akt in nutrient-dependent regulation of cardiac growth. Consistent with this notion, reductions in Akt, 70-kDa S6 kinase 1, and eukaryotic initiation factor 4E-binding protein 1 phosphorylation were observed in mice with cardiac-specific deletion of insulin receptor gene, which exhibit a small heart phenotype. In contrast to wild type animals, caloric restriction in these mice had little effect on Akt phosphorylation in the heart. Furthermore, forced expression of Akt1 in these hearts restored 70-kDa S6 kinase 1 and eukaryotic initiation factor 4E-binding protein 1 phosphorylation to normal levels and rescued the small heart phenotype. Collectively, these results indicate that Akt signaling mediates insulin-dependent physiological heart growth during postnatal development and suggest a mechanism by which heart size is coordinated with overall body size as the nutritional status of the organism is varied.