| 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-ζ/λ 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.Heart failure is a serious life-threatening health problem worldwide. Numerous studies have demonstrated a link between cardiac dysfunction and insulin resistance, as well as deficiency in glucose transport (9, 35, 48). In the absence of manifest diabetes, insulin resistance and minor degrees of glucose intolerance are thought to be associated with and contribute to the development of nonischemic cardiomyopathy or idiopathic dilated cardiomyopathy (35, 45). However, the molecular basis for this link is poorly understood.Muscle-specific gene knockout mice have presented unprecedented opportunities to decipher molecular signaling mechanisms underlying cardiomyopathic changes. Deletion of PTEN in cardiomyocytes mediated by Mck-Cre results in cardiac hypertrophy in mice (8). Dilated cardiomyopathy was also observed to various degrees in mice with conditional ablation of ErbB2 (HER2), β1 integrin, and the gp130 cytokine receptor component in the heart or muscle (16, 34, 37). Interestingly, despite the development of cardiomyopathy, most of these mutant mice survive to adulthood with a normal life span, suggesting limitations in their modeling of human patients'' pathological processes. These mutant mouse models also show no correlation between cardiomyopathy and insulin resistance. In fact, although muscle-specific PTEN knockout mice develop cardiac hypertrophy (8), they are protected against insulin resistance and diabetes induced by high-fat diet due to enhanced insulin-stimulated glucose uptake in soleus muscle (43).Shp2 is a widely expressed cytoplasmic tyrosine phosphatase with two SH2 domains that has been implicated in signaling events downstream of receptors for growth factors, cytokines, and hormones (25, 32). In particular, Shp2 has been shown to participate in leptin and insulin signaling for the regulation of energy balance and metabolism (23, 28, 46). In recent experiments, several groups have identified germ line gain and loss-of-function mutations in the human gene PTPN11, encoding Shp2, in Noonan syndrome and LEOPARD (for lentigines, electrocardiogram abnormalities, ocular hypertelorism, pulmonic valvular stenosis, abnormalities of genitalia, retardation of growth, and deafness) syndrome patients, respectively (21, 42). Paradoxically, these mutations either constitutively activate or inactivate the phosphatase activity leading to heart diseases, among other disorders observed in Noonan or LEOPARD syndrome patients. Since the conventional Shp2 knockout mice are embryonic lethal (36), tissue-specific deletion of Shp2 will be required to determine a specific function for Shp2 in the cardiovascular system in vivo.We report here that striated muscle-specific Shp2 knockout (MSKO) mice develop a severe dilated cardiomyopathy, resulting in heart failure and premature death in mice. More importantly, development of cardiomyopathy is associated with insulin resistance, glucose intolerance, and impaired insulin-stimulated glucose uptake in striated muscle cells in this mouse model. |
