Fiber Type-Specific Nitric Oxide Protects Oxidative Myofibers against Cachectic Stimuli

Oxidative skeletal muscles are more resistant than glycolytic muscles to cachexia caused by chronic heart failure and other chronic diseases. The molecular mechanism for the protection associated with oxidative phenotype remains elusive. We hypothesized that differences in reactive oxygen species (ROS) and nitric oxide (NO) determine the fiber type susceptibility. Here, we show that intraperitoneal injection of endotoxin (lipopolysaccharide, LPS) in mice resulted in higher level of ROS and greater expression of muscle-specific E3 ubiqitin ligases, muscle atrophy F-box (MAFbx)/atrogin-1 and muscle RING finger-1 (MuRF1), in glycolytic white vastus lateralis muscle than in oxidative soleus muscle. By contrast, NO production, inducible NO synthase (iNos) and antioxidant gene expression were greatly enhanced in oxidative, but not in glycolytic muscles, suggesting that NO mediates protection against muscle wasting. NO donors enhanced iNos and antioxidant gene expression and blocked cytokine/endotoxin-induced MAFbx/atrogin-1 expression in cultured myoblasts and in skeletal muscle in vivo. Our studies reveal a novel protective mechanism in oxidative myofibers mediated by enhanced iNos and antioxidant gene expression and suggest a significant value of enhanced NO signaling as a new therapeutic strategy for cachexia

Evidence for a retroviral insertion in TRPM1 as the cause of congenital stationary night blindness and leopard complex spotting in the horse

Leopard complex spotting is a group of white spotting patterns in horses caused by an incompletely dominant gene (LP) where homozygotes (LP/LP) are also affected with congenital stationary night blindness. Previous studies implicated Transient Receptor Potential Cation Channel, Subfamily M, Member 1 (TRPM1) as the best candidate gene for both CSNB and LP. RNA-Seq data pinpointed a 1378 bp insertion in intron 1 of TRPM1 as the potential cause. This insertion, a long terminal repeat (LTR) of an endogenous retrovirus, was completely associated with LP, testing 511 horses (χ²=1022.00, p<<0.0005), and CSNB, testing 43 horses (χ2=43, p<<0.0005). The LTR was shown to disrupt TRPM1 transcription by premature poly-adenylation. Furthermore, while deleterious transposable element insertions should be quickly selected against the identification of this insertion in three ancient DNA samples suggests it has been maintained in the horse gene pool for at least 17,000 years. This study represents the first description of an LTR insertion being associated with both a pigmentation phenotype and an eye disorder.Rebecca R. Bellone … David L. Adelson, Sim Lin Lim … et al

Genotoxicity and histological alterations in grey mullet mugil liza exposed to petroleum water-soluble fraction (PWSF)

Petroleum hydrocarbons are considered one of the main organic chemicals found in water bodies. In the present study, the median lethal concentration (LC50) was estimated for mullet Mugil liza after acute exposure to petroleum watersoluble fraction (PWSF). Furthermore, histopathological studies and micronuclei frequency were also performed in order to observe deleterious effects of medium-term exposition to PWSF. Mullets (25±2.3 g) were exposed to chronic concentrations (1.7, 3.5 and 7 % of PWSF), plus the control group, for 14 and 7 days of clearance time. Throughout the experimental period (1, 4, 14 and 21 days), blood samples were collected for analysis of micronucleus (MN) and liver and gills for histopathological study. For these procedures, seven fish were sampled per concentration tested. The LC50-96 h was estimated at 37.5 % of the PWSF. The time required for MN induction was 96 h of exposure. The time of clearance was sufficient to achieve a MN frequency similar to that of the control group. Histopathological studies showed severe changes in the gill and liver tissues. The most relevant histopathology in the gills was telangiectasia. Hepatic histopathology such as cholestasis, dilated sinusoids and inflammatory infiltrates were commonly described. The MN test and histological study effectively detected damages caused by medium-term exposition to the PWSF, and despite the toxicity, a few days without exposure can minimize PWSF genotoxicity in juveniles of M. liza Remove selecte

Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis

Thoracic aortic aneurysms and dissections are a main feature of connective tissue disorders, such as Marfan syndrome and Loeys-Dietz syndrome. We delineated a new syndrome presenting with aneurysms, dissections and tortuosity throughout the arterial tree in association with mild craniofacial features and skeletal and cutaneous anomalies. In contrast with other aneurysm syndromes, most of these affected individuals presented with early-onset osteoarthritis. We mapped the genetic locus to chromosome 15q22.2-24.2 and show that the disease is caused by mutations in SMAD3. This gene encodes a member of the TGF-beta pathway that is essential for TGF-beta signal transmission(1-3). SMAD3 mutations lead to increased aortic expression of several key players in the TGF-beta pathway, including SMAD3. Molecular diagnosis will allow early and reliable identification of cases and relatives at risk for major cardiovascular complications. Our findings endorse the TGF-beta pathway as the primary pharmacological target for the development of new treatments for aortic aneurysms and osteoarthritis