Fenofibrate unexpectedly induces cardiac hypertrophy in mice lacking MuRF1

The muscle-specific ubiquitin ligase muscle ring finger-1 (MuRF1) is critical in regulating both pathological and physiological cardiac hypertrophy in vivo. Previous work from our group has identified MuRF1's ability to inhibit serum response factor and insulin-like growth factor-1 signaling pathways (via targeted inhibition of cJun as underlying mechanisms). More recently, we have identified that MuRF1 inhibits fatty acid metabolism by targeting peroxisome proliferator-activated receptor alpha (PPARα) for nuclear export via mono-ubiquitination. Since MuRF1−/− mice have an estimated fivefold increase in PPARα activity, we sought to determine how challenge with the PPARα agonist fenofibrate, a PPARα ligand, would affect the heart physiologically. In as little as 3 weeks, feeding with fenofibrate/chow (0.05% wt/wt) induced unexpected pathological cardiac hypertrophy not present in age-matched sibling wild-type (MuRF1 +/+) mice, identified by echocardiography, cardiomyocyte cross-sectional area, and increased beta-myosin heavy chain, brain natriuretic peptide, and skeletal muscle α-actin mRNA. In addition to pathological hypertrophy, MuRF1−/− mice had an unexpected differential expression in genes associated with the pleiotropic effects of fenofibrate involved in the extracellular matrix, protease inhibition, hemostasis, and the sarcomere. At both 3 and 8 weeks of fenofibrate treatment, the differentially expressed MuRF1−/− genes most commonly had SREBP-1 and E2F1/E2F promoter regions by TRANSFAC analysis (54 and 50 genes, respectively, of the 111 of the genes >4 and <−4 log fold change; P≤.0004). These studies identify MuRF1's unexpected regulation of fenofibrate's pleiotropic effects and bridges, for the first time, MuRF1's regulation of PPARα, cardiac hypertrophy, and hemostasis

Biomimetic three-dimensional glioma model printed in vitro for the studies of glioma cells and neurons interactions

The interactions between glioma cells and neurons are important for glioma progression but are rarely mimicked and recapitulated in in vitro three-dimensional (3D) models, which may affect the success rate of relevant drug research and development. In this study, an in vitro bioprinted 3D glioma model consisting of an outer hemispherical shell with neurons and an inner hemisphere with glioma cells is proposed to simulate the natural glioma. This model was produced by extrusion-based 3D bioprinting technology. The cells survival rate, morphology, and intercellular Ca2+ concentration studies were carried out up to 5 days of culturing. It was found that neurons could promote the proliferation of glioma cells around them, associate the morphological changes of glioma cells to be neuron-like, and increase the expression of intracellular Ca2+ of glioma cells. Conversely, the presence of glioma cells could maintain the neuronal survival rate and promote the neurite outgrowth. The results indicated that glioma cells and neurons facilitated each other implying a symbiotic pattern established between two types of cells during the early stage of glioma development, which were seldom found in the present artificial glioma models. The proposed bioprinted glioma model can mimic the natural microenvironment of glioma tissue, provide an in-depth understanding of cellâ cell interactions, and enable pathological and pharmacological studies of glioma.The work was supported by the Program of the National Natural Science Foundation of China [52275291], [51675411], [81972359], the Fundamental Research Funds for the Central Universities, and the Youth Innovation Team of Shaanxi Universities

Cardiac Muscle Ring Finger-1 Increases Susceptibility to Heart Failure In Vivo

Muscle ring finger-1 (MuRF1) is a muscle-specific protein implicated in the regulation of cardiac myocyte size and contractility. MuRF2, a closely related family member, redundantly interacts with protein substrates, and hetero-dimerizes with MuRF1. Mice lacking either MuRF1 or MuRF2 are phenotypically normal whereas mice lacking both proteins develop a spontaneous cardiac and skeletal muscle hypertrophy indicating cooperative control of muscle mass by MuRF1 and MuRF2. In order to identify the unique role that MuRF1 plays in regulating cardiac hypertrophy in vivo, we created transgenic mice expressing increased amounts of cardiac MuRF1. Adult MuRF1 transgenic (Tg+) hearts exhibited a non-progressive thinning of the left ventricular wall and a concomitant decrease in cardiac function. Experimental induction of cardiac hypertrophy by trans-aortic constriction (TAC) induced rapid failure of MuRF1 Tg+ hearts. Microarray analysis identified that the levels of genes associated with metabolism (and in particular mitochondrial processes) were significantly altered in MuRF1 Tg+ hearts, both at baseline and during the development of cardiac hypertrophy. Surprisingly, ATP levels in MuRF1 Tg+ mice did not differ from wild type mice despite the depressed contractility following TAC. In comparing the level and activity of creatine kinase (CK) between wild type and MuRF1 Tg+ hearts we found that mCK and CK-M/B protein levels were unaffected in MuRF1 Tg+ hearts, however total CK activity was significantly inhibited. We conclude that increased expression of cardiac MuRF1 results in a broad disruption of primary metabolic functions, including alterations in CK activity that leads to increased susceptibility to heart failure following TAC. This study demonstrates for the first time a role for MuRF1 in the regulation of cardiac energetics in vivo

Regulation of the calpain and ubiquitin-proteasome systems in a canine model of muscular dystrophy

Previous studies have tested the hypothesis that calpain and/or proteasome inhibition is beneficial in Duchenne Muscular Dystrophy, based largely on evidence that calpain and proteasome activities are enhanced in the mdx mouse

Forming Limit Stress Diagram Prediction of Pure Titanium Sheet Based on GTN Model

In this paper, the initial values of damage parameters in the Gurson&ndash;Tvergaard&ndash;Needleman (GTN) model are determined by a microscopic test combined with empirical formulas, and the final accurate values are determined by finite element reverse calibration. The original void volume fraction (f0), the volume fraction of potential nucleated voids (fN), the critical void volume fraction (fc), the void volume fraction at the final failure (fF) of material are assigned as 0.006, 0.001, 0.03, 0.06 according to the simulation results, respectively. The hemispherical punch stretching test of commercially pure titanium (TA1) sheet is simulated by a plastic constitutive formula derived from the GTN model. The stress and strain are obtained at the last loading step before crack. The forming limit diagram (FLD) and the forming limit stress diagram (FLSD) of the TA1 sheet under plastic forming conditions are plotted, which are in good agreement with the FLD obtained by the hemispherical punch stretching test and the FLSD obtained by the conversion between stress and strain during the sheet forming process. The results show that the GTN model determined by the finite element reverse calibration method can be used to predict the forming limit of the TA1 sheet metal

Constipation in DM are associated with both poor glycemic control and diabetic complications: Current status and future directions

Constipation is a major complications of diabetes mellitus. With the accelerating prevalence of diabetes worldwide and an aging population, there is considerable research interest regarding the altered function and structure of the gastrointestinal tract in diabetic patients. Despite current advances in hyperglycemic treatment strategies, the specific pathogenesis of diabetic constipation remains unknown. Patients with constipation, may be reluctant to eat regularly, which may worsen glycemic control and thus worsen symptoms associated with underlying diabetic bowel disease. This paper presents a review of the complex relationship between diabetes and constipation, exploring the morphological alterations and biomechanical remodeling associated with intestinal motility dysfunction, as well as alterations in intestinal neurons, cellular signaling pathways, and oxidative stress. Further studies focusing on new targets that may play a role in the pathogenesis of diabetic constipation may, provide new ideas for the development of novel therapies to treat or even prevent diabetic constipation