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The insertion/deletion, I/D polymorphism, in the gene encoding Angiotensin Converting Enzyme, ACE is a popular genetic marker for cardiovascular disease, CVD. With alarming rise in diabetes, the risk of CVD among Indian subjects is further enhanced. The present study explored the role of ACE I/D polymorphism, rs4340 as a genetic marker and its association with diabetes. Genomic DNA, isolated from a cohort of 410 urban subjects attending our hospital, was genotyped using polymerase chain reaction followed by electrophoresis. Among the subjects, 84 had type-2 diabetes and 68 had hypertension while 258 were free from these risk factors. Majority (57/84) of diabetic subjects were also suffering from hypertension. Genotype frequencies of ACE I/D polymorphism, of diabetic (84) patients were not different from that of non-diabetic subjects (258). In sharp contrast, we found significant differences, in genotype frequencies of women with diabetes (n = 38) compared to non-diabetic women (70). Diabetic women had significantly higher prevalence of the high risk 'D' allele. Analysis of odds ratio, OR revealed that women with 'D/D' genotype, exhibited threefold risk (OR 3.12, 95% CI 1.21-8.05; p = 0.018) of diabetes, in the recessive model (D/D vs I/I + I/D). Further when we analysed Odds ratio of diabetic women (8) who were free from hypertension, the results revealed even a greater, 6- fold (OR 6.0, 95% CI 1.29-27.96, p = 0.027) risk of diabetes for D/D homozygous women (D/D vs I/I + I/D). These results suggest 'sex-specific' association of ACE 'I/D' polymorphism, with type-2 diabetes, affecting women while there was no influence observed among men. In view of the increased cardiovascular mortality among Indians, data from our pilot study if confirmed in a larger cohort, could add value to our future intervention efforts.
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The role of Reactive Oxygen Species (ROS) on biological media has been shifting over the years, as the knowledge on the complex mechanism that lies in underneath their production and overall results has been growing. It has been known for some time that these species are associated with a number of health conditions. However, they also participate in the immunoactivation cascade process, and can have an active role in theranostics. Macrophages, for example, react to the presence of pathogens through ROS production, potentially allowing the development of new therapeutic strategies. However, their short lifetime and limited spatial distribution of ROS have been limiting factors to the development and understanding of this phenomenon. Even though, ROS have shown successful theranostic applications, e.g., photodynamic therapy, their wide applicability has been hampered by the lack of effective tools for monitoring these processes in real time. Thus the development of innovative sensing strategies for in vivo monitoring of the balance between ROS concentration and the resultant immune response is of the utmost relevance. Such knowledge could lead to major breakthroughs towards the development of more effective treatments for neurodegenerative diseases. Within this review we will present the current understanding on the interaction mechanisms of ROS with biological systems and their overall effect. Additionally, the most promising sensing tools developed so far, for both in vivo and in vitro tracking will be presented along with their main limitations and advantages. This review focuses on the four main ROS that have been studied these are: singlet oxygen species, hydrogen peroxide, hydroxyl radical and superoxide anion.
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Fotoquimioterapia , Superóxidos , Especies Reactivas de Oxígeno , Oxígeno Singlete , Radical HidroxiloRESUMEN
Although rare, breast metastases can mimic primary tumors, both clinically, radiologically, and histopathologically. Melanoma is a highly metastasizing tumor, and it is known as a great mimicker of tumors. Metastatic melanoma in the breast can mimic primary breast cancer and pose a diagnostic challenge. In most cases, it is associated with disseminated disease and a poor prognosis, therefore, histologic, immunohistochemical and clinical correlation is crucial in diagnosing these cases. In this case report, we discuss a 63-year-old female who presented with clinical features of probable breast cancer, describe immunohistochemistry workup, and discuss pitfalls in interpretation.
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Neoplasias de la Mama , Melanoma , Neoplasias Cutáneas , Femenino , Humanos , Persona de Mediana Edad , Melanoma/diagnóstico , Neoplasias de la Mama/diagnóstico , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/patología , InmunohistoquímicaRESUMEN
Three sets of Carbon Dots (Cdots) were produced through the carbohydrates acid thermal decomposition method. These nanoparticles were functionalized with a polymer, known for its biological compatibility: polyethylene glycol, PEG200, and folic acid, FA, a biomolecule associated with the reactive oxygen and nitrogen (ROS/RNS) savaging process, thus resulting CdotsPEG200, CdotsPEG200FA and CdotsFA. These nanoparticles were tested as nitric oxide radical (NO·) sensors and it was determined that CdotsPEG200FA and CdotsFA fluorescence intensity was quenched by the presence of this radical specie. Moreover, according to the Benesi-Hilderbrand plot, the nanoparticles have a high affinity towards the analyte and this interaction is consistent with a 1:1 stoichiometry, through an independent mechanism. The Stern-Volmer constant, obtained for both sensing systems, is compatible with the formation of stable complexes (static quenching) between the Folic Acid residues on the Cdots surface and NO·. The detection and quantification limits along with the sensitivity were calculated for both nanoparticles: DL (31.7 ± 0.02) x 10-9, QL (96.29 ± 0.01) x 10-9, Sensitivity (5.2 ± 0.5) x 109 M for CdotsFA and DL (83 ± 3) x 10-10, QL (251 ± 2) x 10-10, Sensitivity (8.4 ± 0.3) x 1010 M. These values are adequate for biological sensing and are quite competitive with other reported nanosensors for NO· detection and quantification.
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Carbono , Nanopartículas , Carbono/química , Ácido Fólico , Nanopartículas/química , Oxígeno/química , Especies de Nitrógeno ReactivoRESUMEN
Skeletal muscle dysfunction may contribute to the progression and severity of amyotrophic lateral sclerosis (ALS). In the present study, we characterized the skeletal muscle pathophysiology in an inducible transgenic mouse model (rNLS8) that develops a TAR-DNA binding protein (TDP-43) proteinopathy and ALS-like neuropathology and disease progression; representative of >90% of all familial and sporadic ALS cases. As we previously observed elevated levels of miR-23a in skeletal muscle of patients with familial and sporadic ALS, we also investigated the effect of miR-23a suppression on skeletal muscle pathophysiology and disease severity in rNLS8 mice. Five weeks after disease onset TDP-43 protein accumulation was observed in tibialis anterior (TA), quadriceps (QUAD) and diaphragm muscle lysates and associated with skeletal muscle atrophy. In the TA muscle TDP-43 was detected in muscle fibres that appeared atrophied and angular in appearance and that also contained ß-amyloid aggregates. These fibres were also positive for neural cell adhesion molecule (NCAM), but not embryonic myosin heavy chain (eMHC), indicating TDP-43/ ß-amyloid localization in denervated muscle fibres. There was an upregulation of genes associated with myogenesis and NMJ degeneration and a decrease in the MURF1 atrophy-related protein in skeletal muscle. Suppression of miR-23a impaired rotarod performance and grip strength and accelerated body weight loss during early stages of disease progression. This was associated with increased AchRα mRNA expression and decreased protein levels of PGC-1α. The TDP-43 proteinopathy-induced impairment of whole body and skeletal muscle functional performance is associated with muscle wasting and elevated myogenic and NMJ stress markers. Suppressing miR-23a in the rNLS8 mouse model of ALS contributes to an early acceleration of disease progression as measured by decline in motor function.
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Esclerosis Amiotrófica Lateral , Proteínas de Unión al ADN , MicroARNs , Proteinopatías TDP-43 , Esclerosis Amiotrófica Lateral/metabolismo , Animales , Proteínas de Unión al ADN/genética , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Transgénicos , MicroARNs/genética , Proteinopatías TDP-43/genéticaRESUMEN
NEW FINDINGS: What is the central question of this study? Striated muscle activator of rho signalling (STARS) is an actin-binding protein that regulates transcriptional pathways controlling muscle function, growth and myogenesis, processes that are impaired in dystrophic muscle: what is the regulation of the STARS pathway in Duchenne muscular dystrophy (DMD)? What is the main finding and its importance? Members of the STARS signalling pathway are reduced in the quadriceps of patients with DMD and in mouse models of muscular dystrophy. Overexpression of STARS in the dystrophic deficient mdx mouse model increased maximal isometric specific force and upregulated members of the actin cytoskeleton and oxidative phosphorylation pathways. Regulating STARS may be a therapeutic approach to enhance muscle health. ABSTRACT: Duchenne muscular dystrophy (DMD) is characterised by impaired cytoskeleton organisation, cytosolic calcium handling, oxidative stress and mitochondrial dysfunction. This results in progressive muscle damage, wasting and weakness and premature death. The striated muscle activator of rho signalling (STARS) is an actin-binding protein that activates the myocardin-related transcription factor-A (MRTFA)/serum response factor (SRF) transcriptional pathway, a pathway regulating cytoskeletal structure and muscle function, growth and repair. We investigated the regulation of the STARS pathway in the quadriceps muscle from patients with DMD and in the tibialis anterior (TA) muscle from the dystrophin-deficient mdx and dko (utrophin and dystrophin null) mice. Protein levels of STARS, SRF and RHOA were reduced in patients with DMD. STARS, SRF and MRTFA mRNA levels were also decreased in DMD muscle, while Stars mRNA levels were decreased in the mdx mice and Srf and Mrtfa mRNAs decreased in the dko mice. Overexpressing human STARS (hSTARS) in the TA muscles of mdx mice increased maximal isometric specific force by 13% (P < 0.05). This was not associated with changes in muscle mass, fibre cross-sectional area, fibre type, centralised nuclei or collagen deposition. Proteomics screening followed by pathway enrichment analysis identified that hSTARS overexpression resulted in 31 upregulated and 22 downregulated proteins belonging to the actin cytoskeleton and oxidative phosphorylation pathways. These pathways are impaired in dystrophic muscle and regulate processes that are vital for muscle function. Increasing the STARS protein in dystrophic muscle improves muscle force production, potentially via synergistic regulation of cytoskeletal structure and energy production.
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Distrofia Muscular de Duchenne , Fosforilación Oxidativa , Citoesqueleto de Actina/metabolismo , Animales , Modelos Animales de Enfermedad , Distrofina/genética , Distrofina/metabolismo , Humanos , Ratones , Ratones Endogámicos mdx , Proteínas de Microfilamentos , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/metabolismoRESUMEN
The causes of the decline in skeletal muscle mass and function with age, known as sarcopenia, are poorly understood. Nutrition (calorie restriction) interventions impact many cellular processes and increase lifespan and preserve muscle mass and function with age. As we previously observed an increase in life span and muscle function in aging mice on a ketogenic diet (KD), we aimed to investigate the effect of a KD on the maintenance of skeletal muscle mass with age and the potential molecular mechanisms of this action. Twelve-month-old mice were assigned to an isocaloric control or KD until 16 or 26 months of age, at which time skeletal muscle was collected for evaluating mass, morphology, and biochemical properties. Skeletal muscle mass was significantly greater at 26 months in the gastrocnemius of mice on the KD. This result in KD mice was associated with a shift in fiber type from type IIb to IIa fibers and a range of molecular parameters including increased markers of NMJ remodeling, mitochondrial biogenesis, oxidative metabolism, and antioxidant capacity, while decreasing endoplasmic reticulum (ER) stress, protein synthesis, and proteasome activity. Overall, this study shows the effectiveness of a long-term KD in mitigating sarcopenia. The diet preferentially preserved oxidative muscle fibers and improved mitochondrial and antioxidant capacity. These adaptations may result in a healthier cellular environment, decreasing oxidative and ER stress resulting in less protein turnover. These shifts allow mice to better maintain muscle mass and function with age.
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Envejecimiento/fisiología , Dieta Cetogénica/métodos , Músculo Esquelético/metabolismo , Transducción de Señal/fisiología , Animales , Antioxidantes/metabolismo , Estrés del Retículo Endoplásmico/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias Musculares/metabolismo , Unión Neuromuscular/metabolismo , Biogénesis de Organelos , Oxidación-Reducción , Estrés Oxidativo/fisiología , Complejo de la Endopetidasa Proteasomal/metabolismo , Biosíntesis de Proteínas/fisiología , Sarcopenia/dietoterapia , Sarcopenia/metabolismoRESUMEN
Mitochondria have a compartmentalized gene expression system dedicated to the synthesis of membrane proteins essential for oxidative phosphorylation. Responsive quality control mechanisms are needed to ensure that aberrant protein synthesis does not disrupt mitochondrial function. Pathogenic mutations that impede the function of the mitochondrial matrix quality control protease complex composed of AFG3L2 and paraplegin cause a multifaceted clinical syndrome. At the cell and molecular level, defects to this quality control complex are defined by impairment to mitochondrial form and function. Here, we establish the etiology of these phenotypes. We show how disruptions to the quality control of mitochondrial protein synthesis trigger a sequential stress response characterized first by OMA1 activation followed by loss of mitochondrial ribosomes and by remodelling of mitochondrial inner membrane ultrastructure. Inhibiting mitochondrial protein synthesis with chloramphenicol completely blocks this stress response. Together, our data establish a mechanism linking major cell biological phenotypes of AFG3L2 pathogenesis and show how modulation of mitochondrial protein synthesis can exert a beneficial effect on organelle homeostasis.
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Proteasas ATP-Dependientes/genética , Proteasas ATP-Dependientes/metabolismo , ATPasas Asociadas con Actividades Celulares Diversas/genética , ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , Mitocondrias/metabolismo , Proteínas Mitocondriales/biosíntesis , Biosíntesis de Proteínas , Animales , Fibroblastos/metabolismo , GTP Fosfohidrolasas/metabolismo , Técnicas de Silenciamiento del Gen , Células HEK293 , Humanos , Metaloendopeptidasas/metabolismo , Ratones , Membranas Mitocondriales/metabolismo , Ribosomas Mitocondriales/metabolismo , Mutación , Fenotipo , ARN Mensajero/genética , ARN Interferente Pequeño/genética , TransfecciónRESUMEN
Mitochondrial DNA (mtDNA) mutations become more prevalent with age and are postulated to contribute to the ageing process. Point mutations of mtDNA have been suggested to originate from two main sources, i.e. replicative errors and oxidative damage, but the contribution of each of these processes is much discussed. To elucidate the origin of mtDNA mutations, we measured point mutation load in mice with deficient mitochondrial base-excision repair (BER) caused by knockout alleles preventing mitochondrial import of the DNA repair glycosylases OGG1 and MUTYH (Ogg1 dMTS, Mutyh dMTS). Surprisingly, we detected no increase in the mtDNA mutation load in old Ogg1 dMTS mice. As DNA repair is especially important in the germ line, we bred the BER deficient mice for five consecutive generations but found no increase in the mtDNA mutation load in these maternal lineages. To increase reactive oxygen species (ROS) levels and oxidative damage, we bred the Ogg1 dMTS mice with tissue specific Sod2 knockout mice. Although increased superoxide levels caused a plethora of changes in mitochondrial function, we did not detect any changes in the mutation load of mtDNA or mtRNA. Our results show that the importance of oxidative damage as a contributor of mtDNA mutations should be re-evaluated.
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Reparación del ADN , ADN Mitocondrial/química , Estrés Oxidativo , Mutación Puntual , Animales , Núcleo Celular/enzimología , ADN Glicosilasas/metabolismo , Replicación del ADN , Proteínas Hierro-Azufre/antagonistas & inhibidores , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias/enzimología , Proteómica , Superóxido Dismutasa/genética , Transcripción GenéticaRESUMEN
Calorie restriction, without malnutrition, has been shown to increase lifespan and is associated with a shift away from glycolysis toward beta-oxidation. The objective of this study was to mimic this metabolic shift using low-carbohydrate diets and to determine the influence of these diets on longevity and healthspan in mice. C57BL/6 mice were assigned to a ketogenic, low-carbohydrate, or control diet at 12 months of age and were either allowed to live their natural lifespan or tested for physiological function after 1 or 14 months of dietary intervention. The ketogenic diet (KD) significantly increased median lifespan and survival compared to controls. In aged mice, only those consuming a KD displayed preservation of physiological function. The KD increased protein acetylation levels and regulated mTORC1 signaling in a tissue-dependent manner. This study demonstrates that a KD extends longevity and healthspan in mice.
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Dieta Cetogénica , Salud , Longevidad/fisiología , Acetilación , Adaptación Fisiológica , Animales , Dieta Baja en Carbohidratos , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones Endogámicos C57BL , Especificidad de Órganos , Transducción de SeñalRESUMEN
The loss of muscle strength with age has been studied from the perspective of a decline in muscle mass and neuromuscular junction (NMJ) stability. A third potential factor is force transmission. The purpose of this study was to determine the changes in the force transfer apparatus within aging muscle and the impact on membrane integrity and NMJ stability. We measured an age-related loss of dystrophin protein that was greatest in the flexor muscles. The loss of dystrophin protein occurred despite a twofold increase in dystrophin mRNA. Importantly, this disparity could be explained by the four- to fivefold upregulation of the dystromir miR-31. To compensate for the loss of dystrophin protein, aged muscle contained increased α-sarcoglycan, syntrophin, sarcospan, laminin, ß1-integrin, desmuslin, and the Z-line proteins α-actinin and desmin. In spite of the adaptive increase in other force transfer proteins, over the 48 hours following lengthening contractions, the old muscles showed more signs of impaired membrane integrity (fourfold increase in immunoglobulin G-positive fibers and 70% greater dysferlin mRNA) and NMJ instability (14- to 96-fold increases in Runx1, AchRδ, and myogenin mRNA). Overall, these data suggest that age-dependent alterations in dystrophin leave the muscle membrane and NMJ more susceptible to contraction-induced damage even before changes in muscle mass are obvious.
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Envejecimiento/metabolismo , Distrofina/metabolismo , Músculo Esquelético/metabolismo , Enfermedades de la Unión Neuromuscular/metabolismo , Unión Neuromuscular/metabolismo , Animales , Western Blotting , Estimulación Eléctrica , Inmunohistoquímica , Contracción Muscular , Proteínas Musculares/metabolismo , ARN/análisis , Ratas , Ratas Endogámicas F344RESUMEN
Amine-functionalized bridged silsesquioxanes (BSs) were synthesized from bis[(3-trimethoxysilyl)propyl] amine via a solvent-mediated route. BS-1 and BS-2 were obtained at neutral pH with sub- and stoichiometric amounts of water, respectively, and high tetrahydrofuran content. BS-3 was prepared with hyperstoichiometric water concentration, high tetrahydrofuran content, and hydrochloric acid. BS-4 was synthesized with hyperstoichiometric water concentration, high ethanol content, and sodium hydroxide. BS-1 and BS-2 were produced as transparent films, whereas BS-3 and BS-4 formed white powders. Face-to-face stacking of flat or folded lamellae yielded quasi-hydrophobic platelets with emission quantum yields of 0.05 ± 0.01 (BS-1 and BS-2) or superhydrophilic onion-like nanoparticles with exciting emission quantum yields of 0.38 ± 0.03 (BS-3) and 0.33 ± 0.04 (BS-4), respectively. The latter two values are the largest ever reported for amine-functionalized siloxane-based hybrids lacking aromatic groups. Fast Grotthus proton hopping between = [Formula: see text]/ = NH groups (BS-3) and = N-/ = NH groups (BS-4), promoted by H+ and OH- ions, respectively, and aided by short amine-amine contacts provided by the onion-like morphology, account for this unique optical behavior.
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BACKGROUND: Skeletal muscle growth and regeneration depend on the activation of satellite cells, which leads to myocyte proliferation, differentiation and fusion with existing muscle fibers. Skeletal muscle cell proliferation and differentiation are tightly coordinated by a continuum of molecular signaling pathways. The striated muscle activator of Rho signaling (STARS) is an actin binding protein that regulates the transcription of genes involved in muscle cell growth, structure and function via the stimulation of actin polymerization and activation of serum-response factor (SRF) signaling. STARS mediates cell proliferation in smooth and cardiac muscle models; however, whether STARS overexpression enhances cell proliferation and differentiation has not been investigated in skeletal muscle cells. RESULTS: We demonstrate for the first time that STARS overexpression enhances differentiation but not proliferation in C2C12 mouse skeletal muscle cells. Increased differentiation was associated with an increase in the gene levels of the myogenic differentiation markers Ckm, Ckmt2 and Myh4, the differentiation factor Igf2 and the myogenic regulatory factors (MRFs) Myf5 and Myf6. Exposing C2C12 cells to CCG-1423, a pharmacological inhibitor of SRF preventing the nuclear translocation of its co-factor MRTF-A, had no effect on myotube differentiation rate, suggesting that STARS regulates differentiation via a MRTF-A independent mechanism. CONCLUSION: These findings position STARS as an important regulator of skeletal muscle growth and regeneration.
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The decline or recolonization of apex predators such as wolves and lynx, often driven by management decisions, and the expansion of smaller generalist predators such as red foxes, can have important ecosystem impacts. The mesopredator release hypothesis proposes that apex predators control medium-sized predator populations through competition and/or intraguild predation. The decline of apex predators thus leads to an increase in mesopredators, possibly with a negative impact on prey populations. Information about the abundance of mammalian tundra predators, wolf (Canis lupus), wolverine (Gulo gulo), lynx (Lynx lynx), red fox (Vulpes vulpes) and arctic fox (Vulpes lagopus) was collected from local active outdoors people during semi-structured interviews in 14 low arctic or sub-arctic settlements in western Eurasia. The perceived abundance of red fox decreased with higher wolf abundance and in more arctic areas, but the negative effect of wolves decreased in more arctic and therefore less productive ecosystems. The perceived abundance of arctic fox increased towards the arctic and in areas with colder winters. Although there was a negative correlation between the two fox species, red fox was not included in the model for perceived arctic fox abundance, which received most support. Our results support the mesopredator release hypothesis regarding the expansion of red foxes in subarctic areas and indicate that top-down control by apex predators is weaker in less productive and more arctic ecosystems. We showed that local ecological knowledge is a valuable source of information about large-scale processes, which are difficult to study through direct biological investigations.
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Frío , Ecología , Cadena Alimentaria , Zorros , Conducta Predatoria , Tundra , Lobos , Animales , Regiones Árticas , Asia Occidental , Ecosistema , Europa Oriental , Humanos , Lynx , Modelos Teóricos , Mustelidae , Dinámica Poblacional , Estaciones del AñoRESUMEN
The loss of muscle strength and increased injury rate in aging skeletal muscle has previously been attributed to loss of muscle protein (cross-sectional area) and/or decreased neural activation. However, it is becoming clear that force transfer within and between fibers plays a significant role in this process as well. Force transfer involves a secondary matrix of proteins that align and transmit the force produced by the thick and thin filaments along muscle fibers and out to the extracellular matrix. These specialized networks of cytoskeletal proteins aid in passing force through the muscle and also serve to protect individual fibers from injury. This review discusses the cytoskeleton proteins that have been identified as playing a role in muscle force transmission, both longitudinally and laterally, and where possible highlights how disease, aging, and exercise influence the expression and function of these proteins.
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Envejecimiento/fisiología , Ejercicio Físico/fisiología , Fuerza Muscular , Músculo Esquelético/fisiología , Enfermedades Musculares/fisiopatología , Animales , Humanos , Fibras Musculares Esqueléticas/fisiología , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Fuerza Muscular/genética , Soporte de Peso/fisiologíaRESUMEN
Intramuscular creatine plays a crucial role in maintaining skeletal muscle energy homeostasis, and its entry into the cell is dependent upon the sodium chloride dependent Creatine Transporter (CrT; Slc6a8). CrT activity is regulated by a number of factors including extra- and intracellular creatine concentrations, hormones, changes in sodium concentration, and kinase activity, however very little is known about the regulation of CrT gene expression. The present study aimed to investigate how Creatine Transporter (CrT) gene expression is regulated in skeletal muscle. Within the first intron of the CrT gene, we identified a conserved sequence that includes the motif recognized by the Estrogen-related receptor α (ERRα), also known as an Estrogen-related receptor response element (ERRE). Additional ERREs confirming to the known consensus sequence were also identified in the region upstream of the promoter. When partnered with peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PGC-1α) or beta (PGC-1ß), ERRα induces the expression of many genes important for cellular bioenergetics. We therefore hypothesized that PGC-1 and ERRα could also regulate CrT gene expression and creatine uptake in skeletal muscle. Here we show that adenoviral overexpression of PGC-1α or PGC-1ß in L6 myotubes increased CrT mRNA (2.1 and 1.7-fold, P<0.0125) and creatine uptake (1.8 and 1.6-fold, P<0.0125), and this effect was inhibited with co-expression of shRNA for ERRα. Overexpression of a constitutively active ERRα (VP16-ERRα) increased CrT mRNA approximately 8-fold (P<0.05), resulting in a 2.2-fold (P<0.05) increase in creatine uptake. Lastly, chromatin immunoprecipitation assays revealed that PGC-1α and ERRα directly interact with the CrT gene and increase CrT gene expression.
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During the last decade, the striated muscle activator of Rho signaling (STARS), a muscle-specific protein, has been proposed to play an increasingly important role in skeletal muscle growth, metabolism, regeneration and stress adaptation. STARS influences actin dynamics and, as a consequence, regulates the myocardin-related transcription factor A/serum response factor (MRTF-A/SRF) transcriptional program, a well-known pathway controlling skeletal muscle development and function. Muscle-specific stress conditions, such as exercise, positively regulates, while disuse and degenerative muscle diseases are associated with a downregulation of STARS and its downstream partners, suggesting a pivotal role for STARS in skeletal muscle health. This review provides a comprehensive overview of the known role and regulation of STARS and the members of its signaling pathway, RhoA, MRTF-A and SRF, in skeletal muscle.
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Proteínas de Microfilamentos/metabolismo , Músculo Esquelético/fisiología , Transducción de Señal/fisiología , Factores de Transcripción/metabolismo , Animales , HumanosRESUMEN
Knowledge from human exercise studies on regulators of muscle atrophy is lacking, but it is important to understand the underlying mechanisms influencing skeletal muscle protein turnover and net protein gain. This study examined the regulation of muscle atrophy-related factors, including atrogin-1 and MuRF1, their upstream transcription factors FOXO1 and FOXO3A and the atrogin-1 substrate eIF3-f, in response to unilateral isolated eccentric (ECC) vs. concentric (CONC) exercise and training. Exercise was performed with whey protein hydrolysate (WPH) or isocaloric carbohydrate (CHO) supplementation. Twenty-four subjects were divided into WPH and CHO groups and completed both single-bout exercise and 12 wk of training. Single-bout ECC exercise decreased atrogin-1 and FOXO3A mRNA compared with basal and CONC exercise, while MuRF1 mRNA was upregulated compared with basal. ECC exercise downregulated FOXO1 and phospho-FOXO1 protein compared with basal, and phospho-FOXO3A was downregulated compared with CONC. CONC single-bout exercise mediated a greater increase in MuRF1 mRNA and increased FOXO1 mRNA compared with basal and ECC. CONC exercise downregulated FOXO1, FOXO3A, and eIF3-f protein compared with basal. Following training, an increase in basal phospho-FOXO1 was observed. While WPH supplementation with ECC and CONC training further increased muscle hypertrophy, it did not have an additional effect on mRNA or protein levels of the targets measured. In conclusion, atrogin-1, MuRF1, FOXO1/3A, and eIF3-f mRNA, and protein levels, are differentially regulated by exercise contraction mode but not WPH supplementation combined with hypertrophy-inducing training. This highlights the complexity in understanding the differing roles these factors play in healthy muscle adaptation to exercise.
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Ejercicio Físico/fisiología , Factores de Transcripción Forkhead/metabolismo , Proteínas de la Leche/administración & dosificación , Proteínas Musculares/metabolismo , Músculo Esquelético/fisiología , Proteínas Ligasas SKP Cullina F-box/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Administración Oral , Adulto , Suplementos Dietéticos , Proteína Forkhead Box O1 , Proteína Forkhead Box O3 , Factores de Transcripción Forkhead/efectos de los fármacos , Humanos , Masculino , Proteínas de la Leche/farmacocinética , Contracción Muscular/fisiología , Proteínas Musculares/efectos de los fármacos , Acondicionamiento Físico Humano/métodos , Proteínas Ligasas SKP Cullina F-box/efectos de los fármacos , Proteínas de Motivos Tripartitos , Ubiquitina-Proteína Ligasas/efectos de los fármacos , Proteína de Suero de LecheRESUMEN
BACKGROUND AND PURPOSE: Non-small cell lung cancer (NSCLC) is the most common primary tumor in patients developing brain metastasis. This study was performed to develop and validate a survival score particularly for this group of patients. PATIENTS AND METHODS: In this study, the data of 514 patients treated with whole-brain radiotherapy (WBRT) alone for brain metastasis from NSCLC were retrospectively analyzed. The patients were divided into a test group (n = 257) and a validation group (n = 257). In the multivariate analysis of the test group, gender, performance status, and extracranial metastases were independent predictors of survival and, therefore, included in the scoring system. The score for each of the three factors was obtained from the 6-month survival rate (in %) divided by 10. The total scores that represented the sum of the three scores were 5, 8, 9, 11, 12, or 15 points. Three prognostic groups were formed according to the total scores. RESULTS: The 6-month survival rates in the test group were 9 % for 5-9 points (group A), 54 % for 11-12 points (group B), and 79 % for 15 points (group C). In the validation group the 6-month survival rates were 14, 56, and 78 %, respectively. The comparisons between the prognostic groups A, B, and C of the test and the validation group did not reveal any significant differences. CONCLUSION: This new score appears valid and reproducible. It can help predict the survival of patients with brain metastasis from NSCLC.