Skeletal Myogenic Progenitors Originating from Embryonic Dorsal Aorta Coexpress Endothelial and Myogenic Markers and Contribute to Postnatal Muscle Growth and Regeneration

Skeletal muscle in vertebrates is derived from somites, epithelial structures of the paraxial mesoderm, yet many unrelated reports describe the occasional appearance of myogenic cells from tissues of nonsomite origin, suggesting either transdifferentiation or the persistence of a multipotent progenitor. Here, we show that clonable skeletal myogenic cells are present in the embryonic dorsal aorta of mouse embryos. This finding is based on a detailed clonal analysis of different tissue anlagen at various developmental stages. In vitro, these myogenic cells show the same morphology as satellite cells derived from adult skeletal muscle, and express a number of myogenic and endothelial markers. Surprisingly, the latter are also expressed by adult satellite cells. Furthermore, it is possible to clone myogenic cells from limbs of mutant c-Met-/- embryos, which lack appendicular muscles, but have a normal vascular system. Upon transplantation, aorta-derived myogenic cells participate in postnatal muscle growth and regeneration, and fuse with resident satellite cells. The potential of the vascular system to generate skeletal muscle cells may explain observations of nonsomite skeletal myogenesis and raises the possibility that a subset of satellite cells may derive from the vascular system

Akt-mediated phosphorylation controls the activity of the Y-box protein MSY3 in skeletal muscle

Background: The Y-box protein MSY3/Csda represses myogenin transcription in skeletal muscle by binding a highly conserved cis-acting DNA element located just upstream of the myogenin minimal promoter (myogHCE). It is not known how this MSY3 activity is controlled in skeletal muscle. In this study, we provide multiple lines of evidence showing that the post-translational phosphorylation of MSY3 by Akt kinase modulates the MSY3 repression of myogenin. Methods: Skeletal muscle and myogenic C2C12 cells were used to study the effects of MSY3 phosphorylation in vivo and in vitro on its sub-cellular localization and activity, by blocking the IGF1/PI3K/Akt pathway, by Akt depletion and over-expression, and by mutating potential MSY3 phosphorylation sites. Results: We observed that, as skeletal muscle progressed from perinatal to postnatal and adult developmental stages, MSY3 protein became gradually dephosphorylated and accumulated in the nucleus. This correlated well with the reduction of phosphorylated active Akt. In C2C12 myogenic cells, blocking the IGF1/PI3K/Akt pathway using LY294002 inhibitor reduced MSY3 phosphorylation levels resulting in its accumulation in the nuclei. Knocking down Akt expression increased the amount of dephosphorylated MSY3 and reduced myogenin expression and muscle differentiation. MSY3 phosphorylation by Akt in vitro impaired its binding at the MyogHCE element, while blocking Akt increased MSY3 binding activity. While Akt over-expression rescued myogenin expression in MSY3 overexpressing myogenic cells, ablation of the Akt substrate, (Ser126 located in the MSY3 cold shock domain) promoted MSY3 accumulation in the nucleus and abolished this rescue. Furthermore, forced expression of Akt in adult skeletal muscle induced MSY3 phosphorylation and myogenin derepression. Conclusions: These results support the hypothesis that MSY3 phosphorylation by Akt interferes with MSY3 repression of myogenin circuit activity during muscle development. This study highlights a previously undescribed Akt-mediated signaling pathway involved in the repression of myogenin expression in myogenic cells and in mature muscle. Given the significance of myogenin regulation in adult muscle, the Akt/MSY3/myogenin regulatory circuit is a potential therapeutic target to counteract muscle degenerative disease

Atrophy, oxidative switching and ultrastructural defects in skeletal muscle of the ataxia telangiectasia mouse model

Ataxia telangiectasia is a rare, multi system disease caused by ATM kinase deficiency. Atm-knockout mice recapitulate premature aging, immunodeficiency, cancer predisposition, growth retardation and motor defects, but not cerebellar neurodegeneration and ataxia. We explored whether Atm loss is responsible for skeletal muscle defects by investigating myofiber morphology, oxidative/glycolytic activity, myocyte ultrastructural architecture and neuromuscular junctions. Atm-knockout mice showed reduced muscle and fiber size. Atrophy, protein synthesis impairment and a switch from glycolytic to oxidative fibers were detected, along with an increase of in expression of slow and fast myosin types (Myh7, and Myh2 and Myh4, respectively) in tibialis anterior and solei muscles isolated from Atm-knockout mice. Transmission electron microscopy of tibialis anterior revealed misalignments of Z-lines and sarcomeres and mitochondria abnormalities that were associated with an increase in reactive oxygen species. Moreover, neuromuscular junctions appeared larger and more complex than those in Atm wild-type mice, but with preserved presynaptic terminals. In conclusion, we report for the first time that Atm-knockout mice have clear morphological skeletal muscle defects that will be relevant for the investigation of the oxidative stress response, motor alteration and the interplay with peripheral nervous system in ataxia telangiectasia

Impact of soil moisture over Palmer Drought Severity Index and its future projections in Brazil Avaliação da umidade do solo e do Índice de Severidade de Seca de Palmer no Brasil e suas projeções futuras

Soil moisture is a main factor for the study of drought impacts on vegetation. Drought is a regional phenomenon and affects the food security more than any other natural disaster. Currently, the monitoring of different types of drought is based on indexes that standardize in temporal and regional level allowing, thus, comparison of water conditions in different areas. Therefore, in order to assess the impact of soil moisture during periods of drought, drought Palmer Severity Index was estimated for the entire region of the territory. For this were used meteorological data (rainfall and evapotranspiration) and soil (field capacity, permanent wilting point and water storage in the soil). The data field capacity and wilting point were obtained from the physical properties of soil; while the water storage in soil was calculated considering the water balance model. The results of the PSDI were evaluated during the years 2000 to 2015, which correspond to periods with and without occurrence of drought. In order to assess the future drought projections, considering the set of the Coupled Model Intercomparison rainfall data Project Phase 5 (CMIP5). Climate projections precipitation in CMIP5 for the period 2071-2100 was extracted generating entitled forcing scenarios Representative Concentration Pathways - RCPs, and referred to as RCOP 8.5, corresponding to an approximate radiative forcing the end the twenty-first century of 8.5 Wm-2. The results showed that the PDSI is directly associated with climatological patterns of precipitation and soil moisture in any spatial and temporal scale (including future projections). Therefore, it is concluded that the PDSI is an important index to assess soil moisture different water conditions, as well as the association with economic and social information to create risk maps for subsidies to decision makers.Peer ReviewedPostprint (published version

Dynamic Aerobic Exercise Induces Baroreflex Improvement in Diabetic Rats

The objective of the present study was to investigate the effects of an acute aerobic exercise on arterial pressure (AP), heart rate (HR), and baroreflex sensitivity (BRS) in STZ-induced diabetic rats. Male Wistar rats were divided into control (n = 8) and diabetic (n = 8) groups. AP, HR, and BRS, which were measured by tachycardic and bradycardic (BR) responses to AP changes, were evaluated at rest (R) and postexercise session (PE) on a treadmill. At rest, STZ diabetes induced AP and HR reductions, associated with BR impairment. Attenuation in resting diabetes-induced AP (R: 103 ± 2 versus PE: 111 ± 3 mmHg) and HR (R: 290 ± 7 versus PE: 328 ± 10 bpm) reductions and BR dysfunction (R: −0.70 ± 0.06 versus PE: −1.21 ± 0.09 bpm/mmHg) was observed in the postexercise period. In conclusion, the hemodynamic and arterial baro-mediated control of circulation improvement in the postexercise period reinforces the role of exercise in the management of cardiovascular risk in diabetes

Argonaute 2 drives miR-145-5p-dependent gene expression program in breast cancer cells

To perform their regulatory functions, microRNAs (miRNAs) must assemble with any of the four mammalian Argonaute (Ago) family of proteins, Ago1–4, into an effector complex known as the RNA-induced silencing complex (RISC). While the mature miRNA guides the RISC complex to its target mRNA, the Ago protein represses mRNA translation. The specific roles of the various Ago members in mediating miRNAs activity, however, haven’t been clearly established. In this study, we investigated the contribution of Ago2, the only human Ago protein endowed with nuclease activity, to the function of tumor-suppressor miR-145-5p in breast cancer (BC). We show that miR-145-5p and Ago2 protein are concomitantly downregulated in BC tissues and that restoration of miR-145-5p expression in BC cells leads to Ago2 protein induction through the loosening of Ago2 mRNA translational repression. Functionally, miR-145-5p exerts its inhibitory activity on cell migration only in presence of Ago2, while, upon Ago2 depletion, we observed increased miR-145/Ago1 complex and enhanced cell motility. Profiling by microarray of miR-145-5p target mRNAs, in BC cells depleted or not of Ago2, revealed that miR-145-5p drives Ago2-dependent and -independent activities. Our results highlight that the Ago2 protein in cancer cells strictly dictates miR-145-5p tumor suppressor activity

Treinamento físico melhora a disfunção quimiorreflexa em ratos diabéticos por estreptozotocina

The aim of the present study was to investigate the effects of exercise training on arterial pressure, heart rate and chemoreflex sensitivity in STZ-induced diabetic rats. The animals were divided into three groups: control (SC, n = 6), sedentary diabetic (SD, n = 6) and trained diabetic (TD, n = 6). After 1 week of diabetes induction (Streptozotocin, 50 mg/kg, iv), male Wistar rats were submitted to exercise training for 10 weeks on a treadmill. Arterial pressure signals were obtained and processed with a data acquisition system (CODAS, 1 KHz). Potassium cyanide (KCN, 100ug/kg) was used to evaluated bradycardic response evoked by chemoreflex activation. Diabetes bradycardia and hypotension (SD: 274 ± 6 bpm and 94 ± 2 mmHg vs SC: 332 ± 5bpm and 108 ± 2 mmHg) were attenuated by training (TD: 299 ± 5 bpm and 107 ± 2 mmHg). Bradycardic response was decreased in SD rats (33 ± 5 bpm) when compared to SC rats (182 ± 3 bpm) and TD rats (89 ± 10 bpm). In conclusion, exercise training reversed hypotension and bradycardia and improved chemreflex sensitivity in STZ-diabetic rats. Considering that diabetics with abnormal cardiovascular reflexes show higher mortality than diabetics with normal autonomic reflex function, the results obtained suggest that exercise training may contribute to the reduction in cardiovascular risk in this population and must be considered in the management of diabetic patientsO objetivo do presente estudo foi avaliar os efeitos do treinamento físico na pressão arterial, na freq üência cardíaca e na sensibilidade quimiorreflexa em ratos diabéticos por estreptozotocina. Os animais foram divididos em grupos controle (CS, n = 6), diabético sedentário (DS, n = 6) e diabético treinado (DT, n = 6). Uma semana após a indução do diabetes (Estreptozotocina, 50 mg/kg), ratos machos Wistar foram submetidos a um protocolo de treinamento físico em esteira ergométrica por 10 semanas. Os sinais de pressão arterial foram gravados e processados em um sistema de aquisição de dados (CODAS,1KHz). Cianeto de potássio (KCN,100 ug/kg) foi utilizado para avaliar a resposta bradicárdica desencadeada pela estimulação dos quimiorreceptores. A bradicardia e a hipotensão do diabetes (DS:274 ± 6 bpm e 94 ± 2 mmHg vs CS:332 ± 5 bpm e 108 ± 2 mmHg) foram atenuadas pelo treinamento físico (DT:299 ± 5 bpm e 107 ± 2 mmHg). A resposta bradicárdica foi menor nos ratos DS (33 ± 5 bpm) quando comparado aos ratos CS (182 ± 3 bpm) e DT (89 ± 10 bpm). Concluindo, o treinamento físico reverteu a hipotensão e a bradicardia e melhorou a sensibilidade quimioreflexa em ratos STZ. Considerando que diabéticos com reflexos cardiovasculares anormais apresentam maior mortalidade que diabéticos com função reflexa autonômica normal, os resultados obtidos sugerem que o treinamento físico pode contribuir para a redução do risco cardiovascular nesta população devendo ser considerado no manejo do paciente diabétic

PDE2A is indispensable for mouse liver development and hematopoiesis

Phosphodiesterase 2A (PDE2A) is a cAMP-cGMP hydrolyzing enzyme essential for mouse development and the PDE2A knockout model (PDE2A−/−) is embryonic lethal. Notably, livers of PDE2A−/− embryos at embryonic day 14.5 (E14.5) have extremely reduced size. Morphological, cellular and molecular analyses revealed loss of integrity in the PDE2A−/− liver niche that compromises the hematopoietic function and maturation. Hematopoietic cells isolated from PDE2A−/− livers are instead able to differentiate in in vitro assays, suggesting the absence of blood cell-autonomous defects. Apoptosis was revealed in hepatoblasts and at the endothelial and stromal compartments in livers of PDE2A−/− embryos. The increase of the intracellular cAMP level and of the inducible cAMP early repressor (ICER) in liver of PDE2A−/− embryos might explain the impairment of liver development by downregulating the expression of the anti-apoptotic gene Bcl2. In summary, we propose PDE2A as an essential gene for integrity maintenance of liver niche and the accomplishment of hematopoiesis

Avaliação da qualidade vocal de crianças sem queixas vocais: estudo prospectivo duplo-cego

OBJECTIVE: To evaluate the vocal quality of children without voice disorders, analyzing the possible presence and type of lesion, glottic coaptation and laryngeal constriction, roughness and breathiness vocal quality.MATERIALS AND METHODS: We evaluated 50 male children, aged 3 to 10, randomly selected, who did not present otorhinolaryngological disorders. All children went through an otorhinolaryngological exam, followed by videofibrolaryngoscopy and speech pathology evaluation.RESULTS: Out of the 50 children, 25 were classified as normal. Eight presented with cysts, and 17 had vocal nodules. We observed that normal vocal quality was significant in the normal group, while roughness and breathness were associated with the pathological group. We did not find a significant difference in vocal quality when we analyzed glottic coaptation and laryngeal constriction.CONCLUSIONS: Roughness and breathness were significantly associated with structural lesions of the vocal fold, while a normal vocal quality was associated with absence of structural lesions. The authors concluded that all signs of roughness or breathness should be considered in order to allow an early diagnosis of laryngeal alterations and, consequently, early treatment.OBJETIVO: Avaliar a qualidade vocal de crianças que não apresentam queixas de distúrbios na voz. As crianças foram analisadas quanto à possível presença e tipo delesão, quanto ao tipo de coaptação das pregas vocais, e quanto à rouquidão, aspereza e soprosidade da voz.MATERIAIS E MÉTODOS: Foram avalidas 50 crianças do sexo masculino, escolhidas aleatoriamente, na faixa etária de 3 a 10 anos, que não apresentavam queixasotorrinolaringológicas. To das as crianças passaram por exame otorrinolaringológico, seguido de videofibrolaringoscopia e avaliação fonoaudiolóigica.RESULTADOS: Das 50 crianças, 25 foram classificadas como normais. Oito eram portadoras de cisto e 17, portadoras de nódulo vocal, todas sem queixas vocais.Observamos que a qualidade vocal normal esteve presente de maneira significativa no grupo normal, enquanto a rouquidão e a soprosidade estiveram associadas de maneira significativa ao grupo patológico. Nós não observamos diferença significativaquanto a qualidade vocal ao analisarmos a coaptação glótica e a constrição laríngea.CONCLUSÕES: A qualidade vocal do tipo rouca e soprosa está associada de maneira significativa às com lesão estrutural das pregas vocais e a qualidade vocal normal, às crianças sem lesão estrutural. Assim, deve-se atentar para a presença de rouquidão em crianças de forma a permitir o diagnóstico precoce de alterações laríngeas e, conseqüentemente, a terapêutica

Cancer cure for 32 cancer types: results from the EUROCARE-5 study.

BACKGROUND: Few studies have estimated the probability of being cured for cancer patients. This study aims to estimate population-based indicators of cancer cure in Europe by type, sex, age and period. METHODS: 7.2 million cancer patients (42 population-based cancer registries in 17 European countries) diagnosed at ages 15-74 years in 1990-2007 with follow-up to 2008 were selected from the EUROCARE-5 dataset. Mixture-cure models were used to estimate: (i) life expectancy of fatal cases (LEF); (ii) cure fraction (CF) as proportion of patients with same death rates as the general population; (iii) time to cure (TTC) as time to reach 5-year conditional relative survival (CRS) >95%. RESULTS: LEF ranged from 10 years for chronic lymphocytic leukaemia patients to 5 years for women with breast cancer. The CF was 94% for testis, 87% for thyroid cancer in women and 70% in men, 86% for skin melanoma in women and 76% in men, 66% for breast, 63% for prostate and <10% for liver, lung and pancreatic cancers. TTC was <5 years for testis and thyroid cancer patients diagnosed below age 55 years, and <10 years for stomach, colorectal, corpus uteri and melanoma patients of all ages. For breast and prostate cancers, a small excess (CRS < 95%) remained for at least 15 years. CONCLUSIONS: Estimates from this analysis should help to reduce unneeded medicalization and costs. They represent an opportunity to improve patients' quality of life