title: Blocking cardiac growth in hypertrophic cardiomyopathy induces cardiac dysfunction and decreased survival only in males.
abstract: Mutations in myosin heavy chain (MyHC) can cause hypertrophic cardiomyopathy (HCM) that is characterized by hypertrophy, histopathology, contractile dysfunction, and sudden death. The signaling pathways involved in the pathology of HCM have not been elucidated, and an unresolved question is whether blocking hypertrophic growth in HCM may be maladaptive or beneficial. To address these questions, a mouse model of HCM was crossed with an antihypertrophic mouse model of constitutive activated glycogen synthase kinase-3beta (caGSK-3beta). Active GSK-3beta blocked cardiac hypertrophy in both male and female HCM mice. However, doubly transgenic males (HCM/GSK-3beta) demonstrated depressed contractile function, reduced sarcoplasmic (endo) reticulum Ca(2+)-ATPase (SERCA) expression, elevated atrial natriuretic factor (ANF) expression, and premature death. In contrast, female HCM/GSK-3beta double transgenic mice exhibited similar cardiac histology, function, and survival to their female HCM littermates. Remarkably, dietary modification from a soy-based diet to a casein-based diet significantly improved survival in HCM/GSK-3beta males. These findings indicate that activation of GSK-3beta is sufficient to limit cardiac growth in this HCM model and the consequence of caGSK-3beta was sexually dimorphic. Furthermore, these results show that blocking hypertrophy by active GSK-3beta in this HCM model is not therapeutic.
authors.affiliation: Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, Campus Box 347, Boulder, Colorado 80309-0347, USA.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Luckey
authors.forename: Jason
authors.initials: J
authors.lastname: Mansoori
authors.forename: Kelly
authors.initials: K
authors.lastname: Fair
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Antos
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Leinwand
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002312:Cardiomyopathy, Hypertrophic / Q000178:diet therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D003433:Crosses, Genetic; D004044:Dietary Proteins / Q000008:administration & dosage; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009200:Myocardial Contraction; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D012737:Sex Factors; D013997:Time Factors; D020257:Ventricular Remodeling; D000099211:Phospholamban
chemical_list: D000199:Actins; D009320:Atrial Natriuretic Factor; D002135:Calcium-Binding Proteins; D004044:Dietary Proteins; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D018995:Myosin Heavy Chains; D012333:RNA, Messenger; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban; C000605507:Gsk3b protein, mouse