Comparative lipidomic and metabolomic profiling of mdx and severe mdx-apolipoprotein e-null mice.

Despite its notoriously mild phenotype, the dystrophin-deficient mdx mouse is the most common model of Duchenne muscular dystrophy (DMD). By mimicking a human DMD-associated metabolic comorbidity, hyperlipidemia, in mdx mice by inactivating the apolipoprotein E gene (mdx-ApoE) we previously reported severe myofiber damage exacerbation via histology with large fibro-fatty infiltrates and phenotype humanization with ambulation dysfunction when fed a cholesterol- and triglyceride-rich Western diet (mdx-ApoE). Herein, we performed comparative lipidomic and metabolomic analyses of muscle, liver and serum samples from mdx and mdx-ApoE mice using solution and high-resolution-magic angle spinning (HR-MAS) H-NMR spectroscopy.

Apolipoprotein E knockout, but not cholesteryl ester transfer protein (CETP)-associated high-density lipoprotein cholesterol (HDL-C) lowering, exacerbates muscle wasting in dysferlin-null mice.

Background: Dysferlin-deficient limb-girdle muscular dystrophy type 2B (Dysf) mice are notorious for their mild phenotype. Raising plasma total cholesterol (CHOL) via apolipoprotein E (ApoE) knockout (KO) drastically exacerbates muscle wasting in Dysf mice. However, dysferlinopathic patients have abnormally reduced plasma high-density lipoprotein cholesterol (HDL-C) levels.

Losartan and metabolite EXP3179 activate endothelial function without lowering blood pressure in AT2 receptor KO mice.

Background: We have documented profound release of nitric oxide (NO) and endothelium-derived hyperpolarization factor (EDHF) by angiotensin II (ANGII) receptor 1 (AT1) blocker (ARB) losartan and its unique metabolite EXP3179, a pleiotropic effect that may help rationalize the protective properties of ARBs. Since blood pressure (BP) lowering by ARBs likely require an ANGII-dependent switch from AT1 to ANGII receptor 2 (AT2) signaling, a receptor known to stimulate endothelial NO release, we investigated the contribution of AT1 and AT2 to losartan and EXP3179's endothelial function-activating properties.

Experimental Approach: Two AT1 ligands were used in an attempt to block the AT1-dependent endothelium-enhancing effects of EXP3179.

Scaffolds and the scaffolding domain: an alternative paradigm for caveolin-1 signaling.

Caveolin-1 (Cav1) is a 22 kDa intracellular protein that is the main protein constituent of bulb-shaped membrane invaginations known as caveolae. Cav1 can be also found in functional non-caveolar structures at the plasma membrane called scaffolds. Scaffolds were originally described as SDS-resistant oligomers composed of 10-15 Cav1 monomers observable as 8S complexes by sucrose velocity gradient centrifugation.

Humanization of the mdx Mouse Phenotype for Duchenne Muscular Dystrophy Modeling: A Metabolic Perspective.

Duchenne muscular dystrophy (DMD) is a severe form of muscular dystrophy (MD) that is characterized by early muscle wasting and lethal cardiorespiratory failure. While the mdx mouse is the most common model of DMD, it fails to replicate the severe loss of muscle mass and other complications observed in patients, in part due to the multiple rescue pathways found in mice. This led to several attempts at improving DMD animal models by interfering with these rescue pathways through double transgenic approaches, resulting in more severe phenotypes with mixed relevance to the human pathology.