title: Deletion of Shp2 tyrosine phosphatase in muscle leads to dilated cardiomyopathy, insulin resistance, and premature death.
abstract: The intracellular signaling mechanisms underlying the pathogenesis of cardiac diseases are not fully understood. We report here that selective deletion of Shp2, an SH2-containing cytoplasmic tyrosine phosphatase, in striated muscle results in severe dilated cardiomyopathy in mice, leading to heart failure and premature mortality. Development of cardiomyopathy in this mouse model is coupled with insulin resistance, glucose intolerance, and impaired glucose uptake in striated muscle cells. Shp2 deficiency leads to upregulation of leukemia inhibitory factor-stimulated phosphatidylinositol 3-kinase/Akt, Erk5, and Stat3 pathways in cardiomyocytes. Insulin resistance and impaired glucose uptake in Shp2-deficient mice are at least in part due to impaired protein kinase C-zeta/lambda and AMP-kinase activities in striated muscle. Thus, we have generated a mouse line modeling human patients suffering from cardiomyopathy and insulin resistance. This study reinforces a concept that a compound disease with multiple cardiovascular and metabolic disturbances can be caused by a defect in a single molecule such as Shp2, which modulates multiple signaling pathways initiated by cytokines and hormones.
authors.affiliation: Burnham Institute for Medical Research, 10901 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
authors.forename: Frederic
authors.initials: F
authors.lastname: Princen
authors.forename: Emilie
authors.initials: E
authors.lastname: Bard
authors.forename: Farah
authors.initials: F
authors.lastname: Sheikh
authors.forename: Sharon S
authors.initials: SS
authors.lastname: Zhang
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Wagner M
authors.initials: WM
authors.lastname: Zago
authors.forename: Dongmei
authors.initials: D
authors.lastname: Wu
authors.forename: Ramon Diaz
authors.initials: RD
authors.lastname: Trelles
authors.forename: Beatrice
authors.initials: B
authors.lastname: Bailly-Maitre
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Kahn
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
authors.forename: Gary G
authors.initials: GG
authors.lastname: Tong
authors.forename: Mark
authors.initials: M
authors.lastname: Mercola
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
authors.forename: Gen-Sheng
authors.initials: GS
authors.lastname: Feng
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017353:Gene Deletion; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000503:physiopathology; D007333:Insulin Resistance / Q000235:genetics; D053208:Kaplan-Meier Estimate; D053605:Leukemia Inhibitory Factor / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D048054:Mitogen-Activated Protein Kinase 7; D020930:MAP Kinase Kinase Kinases; C087095:insulin-stimulated MEK kinase; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse; D005947:Glucose