Development of dilated cardiomyopathy and impaired calcium homeostasis with cardiac-specific deletion of ESRRß.

Mechanisms underlying the development of idiopathic dilated cardiomyopathy (DCM) remain poorly understood. Using transcription factor expression profiling, we identified estrogen-related receptor-ß (ESRRß), a member of the nuclear receptor family of transcription factors, as highly expressed in murine hearts and other highly oxidative striated muscle beds. Mice bearing cardiac-specific deletion of ESRRß (MHC-ERRB KO) develop DCM and sudden death at ~10 mo of age. Isolated adult cardiomyocytes from the MHC-ERRB KO mice showed an increase in calcium sensitivity and impaired cardiomyocyte contractility, which preceded echocardiographic cardiac remodeling and dysfunction by several months. Histological analyses of myocardial biopsies from patients with various cardiomyopathies revealed that ESRRß protein is absent from the nucleus of cardiomyocytes from patients with DCM but not other forms of cardiomyopathy (ischemic, hypertrophic, and arrhythmogenic right ventricular cardiomyopathy). Taken together these observations suggest that ESRRß is a critical component in the onset of DCM by affecting contractility and calcium balance.NEW & NOTEWORTHY Estrogen-related receptor-ß (ESRRß) is highly expressed in the heart and cardiac-specific deletion results in the development of a dilated cardiomyopathy (DCM). ESRRß is mislocalized in human myocardium samples with DCM, suggesting a possible role for ESRRß in the pathogenesis of DCM in humans.

Pathological role of serum- and glucocorticoid-regulated kinase 1 in adverse ventricular remodeling.

BACKGROUND: Heart failure is a growing cause of morbidity and mortality. Cardiac phosphatidylinositol 3-kinase signaling promotes cardiomyocyte survival and function, but it is paradoxically activated in heart failure, suggesting that chronic activation of this pathway may become maladaptive. Here, we investigated the downstream phosphatidylinositol 3-kinase effector, serum- and glucocorticoid-regulated kinase-1 (SGK1), in heart failure and its complications. METHODS AND RESULTS: We found that cardiac SGK1 is activated in human and murine heart failure. We investigated the role of SGK1 in the heart by using cardiac-specific expression of constitutively active or dominant-negative SGK1. Cardiac-specific activation of SGK1 in mice increased mortality, cardiac dysfunction, and ventricular arrhythmias. The proarrhythmic effects of SGK1 were linked to biochemical and functional changes in the cardiac sodium channel and could be reversed by treatment with ranolazine, a blocker of the late sodium current. Conversely, cardiac-specific inhibition of SGK1 protected mice after hemodynamic stress from fibrosis, heart failure, and sodium channel alterations. CONCLUSIONS: SGK1 appears both necessary and sufficient for key features of adverse ventricular remodeling and may provide a novel therapeutic target in cardiac disease.

Impact of exercise on muscle and nonmuscle organs.

Exercise is known to prevent and treat metabolic diseases such as diabetes. However, the underlying mechanisms are not fully understood, and there is currently much focus on detailing such pathways. Traditionally, much emphasis has been placed on skeletal muscle; however, recently, nonmuscle organs such as adipose tissue have been highlighted in mediating protective actions after training. Moreover, novel paracrine- and endocrine-signaling molecules have been shown to trigger important responses in nonmuscle organs after exercise. This is exciting because, when administered exogenously, such signals have obvious therapeutic potential. In this review, the authors have described some general and historical aspects of training and disease protection. The authors have also highlighted some of the current knowledge on how exercise impacts nonmuscle organs.