In many cells and specially in muscle, mitochondria form elongated filaments or a branched reticulum. We show that Mfn2 (mitofusin 2), a mitochondrial membrane protein that participates in mitochondrial fusion in mammalian cells, is induced during myogenesis and contributes to the maintenance and operation of the mitochondrial network. Repression of Mfn2 caused morphological and functional fragmentation of the mitochondrial network into independent clusters. Concomitantly, repression of Mfn2 reduced glucose oxidation, mitochondrial membrane potential, cell respiration, and mitochondrial proton leak. We also show that the Mfn2-dependent mechanism of mitochondrial control is disturbed in obesity by reduced Mfn2 expression. In all, our data indicate that Mfn2 expression is crucial in mitochondrial metabolism through the maintenance of the mitochondrial network architecture, and reduced Mfn2 expression may explain some of the metabolic alterations associated with obesity.
Abstract-We evaluated the association between salt-sensitive hypertension and 3 different genetic polymorphisms of the renin-angiotensin system. Fifty patients with essential hypertension were classified as salt sensitive or salt resistant, depending on the presence or absence of a significant increase (PϽ0.05) in 24-hour ambulatory mean blood pressure (BP) after high salt intake. Key Words: angiotensin-converting enzyme Ⅲ genes Ⅲ angiotensin II Ⅲ blood pressure monitoring, ambulatory T he blood pressure (BP) response to increased dietary salt is heterogeneous among individuals, a phenomenon known as salt sensitivity. Normotensive and hypertensive salt-sensitive subjects tend to exhibit familial history of hypertension more frequently than salt-resistant subjects. 1,2 This suggests the existence of genetic determinants that influence BP sensitivity to sodium chloride. More than 10 years ago, Weinberger et al 3 reported a significant relation between haptoglobin 1-1 phenotype and BP response to intravenous sodium overload both in normotensive and hypertensive subjects.The renin-angiotensin system (RAS) has a central role in controlling BP and sodium homeostasis. 4 In the last decade, several authors have investigated RAS polymorphisms as genetic determinants of essential hypertension and end-organ damage. Although the results obtained are controversial, the presence of the D allele in intron 16 of the angiotensinconverting enzyme (ACE) gene appears to be associated with a higher risk for development of both macrovascular and microvascular disease in hypertensive individuals. 5 Moreover, the presence of the T allele in exon 2 of the angiotensinogen (AGT) gene appears to be associated with a higher risk for development of hypertension. 6 Finally, the association of the T allele of the AGT gene and the D allele of the ACE gene has a synergistic effect on the incidence of cerebrovascular disease, 7 and the association of the D allele of the ACE gene and the C allele of angiotensin II type 1 (AT1) receptor gene appears to increase the risk of myocardial infarction. 8 The RAS also is implicated in the BP response to salt intake. Low-renin hypertensives show an increased BP response to NaCl load, 9 and salt-sensitive individuals exhibit a blunted response of the RAS when they switch from low to high salt intake compared with salt-resistant subjects. 10 Moreover, plasma levels of ACE and angiotensinogen differ in subjects with different ACE and angiotensinogen genotypes. 11,12
BackgroundDiabetes is characterized by reduced thyroid function and altered myogenesis after muscle injury. Here we identify a novel component of thyroid hormone action that is repressed in diabetic rat muscle.Methodology/Principal FindingsWe have identified a gene, named DOR, abundantly expressed in insulin-sensitive tissues such as skeletal muscle and heart, whose expression is highly repressed in muscle from obese diabetic rats. DOR expression is up-regulated during muscle differentiation and its loss-of-function has a negative impact on gene expression programmes linked to myogenesis or driven by thyroid hormones. In agreement with this, DOR enhances the transcriptional activity of the thyroid hormone receptor TRα1. This function is driven by the N-terminal part of the protein. Moreover, DOR physically interacts with TR α1 and to T3-responsive promoters, as shown by ChIP assays. T3 stimulation also promotes the mobilization of DOR from its localization in nuclear PML bodies, thereby indicating that its nuclear localization and cellular function may be related.Conclusions/SignificanceOur data indicate that DOR modulates thyroid hormone function and controls myogenesis. DOR expression is down-regulated in skeletal muscle in diabetes. This finding may be of relevance for the alterations in muscle function associated with this disease.
An insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene significantly influences circulating ACE levels and plays a role in the development of target organ damage, that is, left ventricular hypertrophy in essential hypertension (EH), and microalbuminuria in diabetes mellitus. We have examined the role of the I/D polymorphism in essential hypertensive patients with renal involvement. The study was divided in two independent protocols. In protocol 1, we retrospectively analyzed the ACE genotypes in 37 essential hypertensive patients with a clinical and histopathological diagnosis of nephroangiosclerosis. In protocol 2, ACE genotypes as well as microalbuminuria and renal hemodynamic parameters were investigated in 75 patients with EH with normal renal function and a strong family history of hypertension. As control group, 75 healthy subjects with BP < 130/85 mm Hg and no family history of cardiovascular diseases were studied. The ACE variants were determined by PCR and the genotypes were classified as DD, DI and II. In protocol 1, patients with nephroangiosclerosis displayed a significant difference in the genotype distribution (57% DD, 27% DI, 16% II) when compared to the control population (25% DD, 64% DI, 11% II; P < 0.001). There was no significant difference in genotype distribution between hypertensive patients with normal renal function (protocol 2; 33% DD, 59% DI, 8% II) and the control group. There were no differences in age, blood pressure, microalbuminuria and duration of the disease among the three genotypes in the EH group from protocol 2. Taken together, these findings suggest that the DD genotype of ACE is associated with histopathologic-proven kidney involvement in patients with EH and that this polymorphism could be a potential genetic marker in hypertensives at risk of renal complications.
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