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.

journal_name

Mol Cell Biol

authors

Princen F,Bard E,Sheikh F,Zhang SS,Wang J,Zago WM,Wu D,Trelles RD,Bailly-Maitre B,Kahn CR,Chen Y,Reed JC,Tong GG,Mercola M,Chen J,Feng GS

doi

10.1128/MCB.01661-08

subject

Has Abstract

pub_date

2009-01-01 00:00:00

pages

378-88

issue

2

eissn

0270-7306

issn

1098-5549

pii

MCB.01661-08

journal_volume

29

pub_type

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