Akt signaling mediates postnatal heart growth in response to insulin and nutritional status.
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.
Shiojima
Ichiro
I
Molecular Cardiology/Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Yefremashvili
Mikkael
M
Luo
Zhengyu
Z
Kureishi
Yasuko
Y
Takahashi
Akihiro
A
Tao
Jingzang
J
Rosenzweig
Anthony
A
Kahn
C Ronald
CR
Abel
E Dale
ED
Walsh
Kenneth
K
D000375:Aging / Q000502:physiology*; D000818:Animals; D006332:Cardiomegaly / Q000503:physiopathology; D002478:Cells, Cultured; D004790:Enzyme Induction; D005215:Fasting; D005838:Genotype; D006321:Heart / Q000187:drug effects / Q000254:growth & development*; D007328:Insulin / Q000494:pharmacology*; D007930:Leucine / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D009206:Myocardium / Q000166:cytology; D009752:Nutritional Status / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism
D007328:Insulin; D011518:Proto-Oncogene Proteins; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D007930:Leucine