No abstract

No abstract

Mutations in TAB2 (transforming growth factor β activated kinase 1 binding protein 2) have been implicated in the pathogenesis of dilated cardiomyopathy and/or congenital heart disease in humans, but the underlying mechanisms are currently unknown. Here we identified an indispensable role for TAB2 in regulating myocardial homeostasis and remodeling by suppressing RIPK1 (receptor-interacting protein kinase 1) activation and RIPK1-dependent apoptosis and necroptosis. Cardiomyocyte-specific deletion of Tab2 in mice triggered dilated cardiomyopathy with massive apoptotic and necroptotic cell death. Moreover, Tab2-deficient mice were also predisposed to myocardial injury and adverse remodeling following pathological stress. In cardiomyocytes, deletion of TAB2, but not its close homologue TAB3, promoted TNFa-induced apoptosis and necroptosis, which was rescued by forced activation of TAK1 or inhibition of RIPK1 kinase activity. Mechanistically, TAB2 critically mediates RIPK1 phosphorylation at Ser321 via a TAK1-dependent mechanism, which prevents RIPK1 kinase activation and the formation of RIPK1-FADD-caspase-8 apoptotic complex or RIPK1-RIPK3 necroptotic complex. Strikingly, genetic inactivation of RIPK1 with Ripk1-K45A knock-in effectively rescued cardiac remodeling and dysfunction in Tab2-deficient mice. Together, these data demonstrate that TAB2 is a key regulator of myocardial homeostasis and remodeling by suppressing RIPK1-dependent apoptosis and necroptosis. Our results also suggest that targeting RIPK1-mediated cell death signaling may represent a promising therapeutic strategy for TAB2 deficiency-induced dilated cardiomyopathy.

Objective: This study was designed to compare the clinical manifestations, laboratory tests, etiology, and prognosis of children with acute rhabdomyolysis (RM) at various ages. This study was designed to analyze the risk factors for acute kidney injury (AKI) in children with RM and to identify the role of neuromuscular and autoimmune disease in children with RM. Methods: Clinical data for 55 children with RM were collected and statistically analyzed. Patients were stratified to an infant group (G1) (age <1 year), preschool group (G2) (age 1-6 year), school-age group (G3) (age 7-11 year), and an adolescent group (G4) (age 12-16 year). Results: The top three clinical manifestations were dark urine (52.7%), myalgia (38.2%), and fever (23.8%). Patients in G1 had fever (71.4%), vomiting (77.8%), and urinalysis abnormalities (14.3%), without triad clinical manifestations. Fifty percent of patients in G4 group had myalgia; 70.8% had dark urine; 75% had abnormal urine tests. The most common cause in each age group was as follows: sepsis (57.1%) in G1; hereditary neuromuscular diseases (44.4%) in G2; immune diseases (40%) in G3; strenuous exercise (50%) in G4. Logistic regression analysis shown that AKI was not corelated with age, gender, or peak creatine phosphokinase. AKI was, however, associated with presence of an electrolyte disorder. Conclusion: The clinical manifestations and laboratory findings in infants with acute RM are not typical and need to be taken seriously. The presence of an electrolyte disorder is a risk factor for AKI in children with RM. The most common pathogenesis of RM varies among age groups. Congenital hereditary metabolic disease and immune diseases should not be ignored as a cause of RM in children.