title: Deficiency of insulin-like growth factor 1 reduces sensitivity to aging-associated cardiomyocyte dysfunction.
abstract: Circulating insulin-like growth factor-1 (IGF-1) levels are linked to cardiac performance and lifespan. However, the role of IGF-1 levels in aging-associated cardiac dysfunction has not been defined. This study was designed to evaluate the impact of severe liver IGF-1 deficiency (LID) on aging-induced cardiomyocyte contractile and intracellular Ca(++) dysfunction. Cardiomyocytes were isolated from young (2- to 4-month-old) and old (24- to 26-month-old) male C57BL/6 and LID mice. Cardiomyocyte contractile and intracellular Ca(++) transient properties were evaluated, including peak shortening (PS), maximal velocity of shortening/relengthening (+/-dL/dt), time-to-PS (TPS), time-to-90% relengthening (TR(90)), electrically stimulated change in fura-fluorescence intensity (DeltaFFI), and intracellular Ca(++) decay rate. Aged C57BL/6 myocytes displayed reduced PS, +/-dL/dt and DeltaFFI as well as prolonged TR(90) and intracellular Ca(++) decay. IGF-1 deficiency decreased +/-dL/dt, and prolonged TR(90) with little change in other mechanical indices. Interestingly, LID dampened aging-induced changes in cardiomyocyte function. Aging and IGF-1 deficiency both contributed to whole-body glucose intolerance. Aging downregulated expression of Akt, Klotho, and pAMPK, whereas it upregulated p53 expression, the effects of which were cancelled by IGF-1 deficiency. Aging and IGF-1 deficiency significantly reduced expression of the transcriptional factor Foxo3a without an overt effect on the mammalian target of rapamycin (mTOR) level. Collectively, these data depicted that IGF-1 deficiency may reduce the cardiomyocyte sensitivity to aging-induced mechanical dysfunction. Our data suggest that regulation of Akt, p53, adenosine monophosphate-activated protein kinase (AMPK) phosphorylation, and Klotho may play a role, at least in part, in IGF-1 deficiency-induced "desensitization" of cardiac aging.
authors: Division of Pharmaceutical Sciences & Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY 82071, USA.
authors: Qun
authors: Q
authors: Li
authors: Asli F
authors: AF
authors: Ceylan-Isik
authors: Ji
authors: J
authors: Li
authors: Jun
authors: J
authors: Ren
mesh_terms: D055372:AMP-Activated Protein Kinases; D000375:Aging / Q000235:genetics / Q000473:pathology*; D000818:Animals; D020013:Calcium Signaling / Q000502:physiology; D009202:Cardiomyopathies / Q000235:genetics* / Q000473:pathology; D020022:Genetic Predisposition to Disease; D005951:Glucose Tolerance Test; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D000090265:Klotho Proteins; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D009200:Myocardial Contraction / Q000235:genetics / Q000502:physiology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D009097:Multienzyme Complexes; D016159:Tumor Suppressor Protein p53; D007334:Insulin-Like Growth Factor I; D051058:Oncogene Protein v-akt; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005966:Glucuronidase; D000090265:Klotho Proteins