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Folic acid fortification of all white flour, enriched pasta, and cornmeal products became mandatory in Canada to reduce risk of neural tube defects at birth. Furthermore, Health Canada and the Society of Obstetricians and Gynaecologists of Canada recommend women take daily prenatal folic acid supplements in addition to folic acid fortified foods during pregnancy. However, the influence of maternal folic acid supplementation on offspring development, specifically the highly abundant and metabolically active skeletal muscle, is currently unknown. Thus, the purpose of this study was to determine the effect of supplemental folic acid (four times higher than normal dietary consumption), in utero and throughout suckling on muscle size, function, and metabolism in male and female CD-1 mouse offspring. The major findings were that maternal exposure to supplemental folic acid (i) had no impact on postpartum growth rates or muscle mass in female and male offspring, (ii) had no impact on skeletal muscle contractile kinetics in females and male offspring, and (iii) increased maximal phosphofructokinase activity in extensor digitorum longus of female and male offspring. These findings suggest that exposure to folic acid supplementation in utero and throughout suckling at levels four times higher than recommended had minimal effect on skeletal muscle size, function, and metabolism regardless of sex. Future research is needed explore the underlying biological pathways and mechanisms affected by folic acid supplementation during pregnancy and lactation on offspring skeletal muscle tissue, specifically in humans.
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Contracción Muscular , Músculo Esquelético , Embarazo , Femenino , Masculino , Humanos , Animales , Ratones , Fosforilación , Ácido Fólico/farmacología , Suplementos DietéticosRESUMEN
Exercise reduces cognitive aging, neurodegeneration, and Alzheimer's disease (AD) risk. Acute exercise reduces the activity of ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1), the rate-limiting enzyme in the production of Aß. However, mechanisms mediating these effects remain largely unknown. Work has implicated brain-derived neurotrophic factor (BDNF) in the processing of amyloid precursor protein (APP). BDNF is an exercise-induced neurotrophin known for its role in synaptic plasticity, neurite growth, and neuronal survival. Previously, our lab has shown using an ex vivo model that treatment of the prefrontal cortex with BDNF reduced BACE1 activity, highlighting a BDNF to BACE1 link. The purpose of this research was to examine whether BDNF treatments resulted in similar biochemical adaptations to APP processing as exercise training. Male C57BL6/J mice were assigned into one of four groups (n = 12/group): 1) control; 2) exercise training (progressive treadmill training 5 days/wk); 3) BDNF (0.5 mg/kg body mass subcutaneous injection 5 days/wk); or 4) endurance training and BDNF, for an 8-wk intervention. Recognition memory was measured with a novel object recognition test. Serum, the prefrontal cortex, and hippocampus were collected. BDNF improved recognition memory to a similar extent as endurance training. BDNF and exercise decreased BACE1 activity and increased ADAM10 activity in the prefrontal cortex, indicating a shift in APP processing. Our novel results indicate that BDNF exerts similar beneficial effects on cognition and APP processing as exercise training. Future evidence-based preventative or therapeutic interventions that increase BDNF and reduce BACE1 will be of value for populations that are at risk of AD.NEW & NOTEWORTHY Our study presents the novel findings that chronic peripheral BDNF injections result in regulation of APP processing enzymes and improved cognition to a similar extent as exercise training. These findings highlight the potential efficacy of using BDNF as a therapeutic intervention in the prevention of neurodegenerative diseases (i.e., Alzheimer's disease). Furthermore, future evidence-based preventative or therapeutic interventions that increase BDNF and reduce BACE1 will be of value for populations that are at risk of AD.
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Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide , Ratones , Animales , Masculino , Precursor de Proteína beta-Amiloide/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Factor Neurotrófico Derivado del Encéfalo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidasas/metabolismo , Cognición , Ratones TransgénicosRESUMEN
PURPOSE: Sepsis remains a life-threatening condition and leading cause of death in the United States despite vast efforts to understand and treat it. Successful sepsis treatment requires the timely implementation of the sepsis bundle to avoid multiple organ system failure; a key component of sepsis care is nursing surveillance. The purpose of this study was to explore nurses' knowledge of nursing surveillance related to the patient with sepsis and to describe barriers to the implementation of nursing surveillance for sepsis and the sepsis bundle. DESIGN: A qualitative descriptive design study used focus groups to elicit responses to open-ended questions. METHODS: Focus group interviews with 28 registered nurses were conducted. All focus group participants had a minimum of 6 months' experience caring for patients with sepsis. RESULTS: Five themes emerged from the study: (1) knowledge deficit of the sepsis bundle and nursing surveillance, (2) uncertain and overwhelmed, (3) lack of resources, (4) in the dark, and (5) lack of partnership/respect. The notion of fearing the patient with sepsis and knowledge deficits of nursing surveillance and sepsis bundle were unique findings. CONCLUSIONS: Findings highlight the need for increased attention on the importance of nurse surveillance of the patient with sepsis.
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Enfermeras y Enfermeros , Sepsis , Humanos , Estados Unidos , Competencia Clínica , Investigación Cualitativa , Grupos Focales , Sepsis/diagnósticoRESUMEN
Barth syndrome is a rare and incurable X-linked (male-specific) genetic disease that affects the protein tafazzin (Taz). Taz is an important enzyme responsible for synthesizing biologically relevant cardiolipin (for heart and skeletal muscle, cardiolipin rich in linoleic acid), a critical phospholipid of mitochondrial form and function. Mutations to Taz cause dysfunctional mitochondria, resulting in exercise intolerance due to skeletal muscle weakness. To date, there has been limited research on improving skeletal muscle function, with interventions focused on endurance and resistance exercise. Previous cell culture research has shown therapeutic potential for the addition of exogenous linoleic acid in improving Taz-deficient mitochondrial function but has not been examined in vivo. The purpose of this study was to examine the influence of supplemental dietary linoleic acid on skeletal muscle function in a rodent model of Barth syndrome, the inducible Taz knockdown (TazKD) mouse. One of the main findings was that TazKD soleus demonstrated an impaired contractile phenotype (slower force development and rates of relaxation) in vitro compared to their WT littermates. Interestingly, this impaired contractile phenotype seen in vitro did not translate to altered muscle function in vivo at the whole-body level. Also, supplemental linoleic acid attenuated, to some degree, in vitro impaired contractile phenotype in TazKD soleus, and these findings appear to be partially mediated by improvements in cardiolipin content and resulting mitochondrial supercomplex formation. Future research will further examine alternative mechanisms of dietary supplemental LA on improving skeletal muscle contractile dysfunction in TazKD mice.
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Skeletal muscle is composed of fiber types that differ in mitochondrial content, antioxidant capacity, and susceptibility to apoptosis. Ceramides have been linked to oxidative stress-mediated apoptotic intracellular signalling and the enzyme neutral sphingomyelinase (nSMase) is, in part, responsible for generating these ceramides through the hydrolysis of sphingomyelin. Despite the role of ceramides in mediating apoptosis, there is a gap in the literature regarding nSMase in skeletal muscle mitochondria. This study aimed to characterize total nSMase activity and individual isoform expression in isolated subsarcolemmal (SS) mitochondria from soleus, diaphragm, plantaris, and extensor digitorum longus (EDL). Total nSMase activity did not differ between muscle types. nSMase2 content was detectable in all muscles and higher in EDL, soleus, and plantaris compared to diaphragm whereas nSMase3 was undetectable in all muscles. Finally, total nSMase activity positively correlated to nSMase2 protein content in soleus but not the other muscles. These findings suggest that nSMase associated with SS mitochondria may play a role in intracellular signalling processes involving ceramides in skeletal muscle and nSMase2 may be the key isoform, specifically in slow twitch muscle like soleus. Further studies are needed to fully elucidate the specific contribution of nSMase, along with the role of the various isoforms and mitochondrial subpopulation in generating mitochondrial ceramides in skeletal muscle, and its potential effects on mediating apoptosis.
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Mitocondrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Esfingomielina Fosfodiesterasa/metabolismo , Animales , Diafragma/metabolismo , Regulación de la Expresión Génica , Masculino , Oxazinas/metabolismo , RatasRESUMEN
Allergic inflammatory diseases are a steadily growing health concern. Mast cells, a driving force behind allergic pathologies, modulate metabolic pathways to carry out various functions following IgE-FcεRI-mediated activation. Tafazzin (TAZ) is a cardiolipin transacylase that functions to remodel, and thereby mature, cardiolipin, which is important for efficient energy production through oxidative phosphorylation. In this study, we aimed to evaluate the contribution of TAZ in IgE-mediated mast cell activation. Fetal liver-derived mast cells (FLMCs) were differentiated from mice with a doxycycline (dox)-inducible TAZ short hairpin RNA (shRNA) cassette (TAZ shRNA+/+) and littermate wild-types (WTs). TAZ knockdown in FLMCs following dox treatment was confirmed by Western blotting (99.1% by day 5), whereas flow cytometry confirmed FLMC phenotype (c-kit+ FcεRI+) and retention of receptor expression post-dox. Five-day dox-treated WT and TAZ shRNA+/+ FLMCs were activated via allergen-bound IgE cross-linking of FcεRI under stem cell factor potentiation. With dox, and in response to allergen, TAZ shRNA+/+ FLMCs displayed a 25% reduction in oxygen consumption and a significant 31% reduction in mast cell degranulation compared with dox-treated WT FLMCs. Secretion of TNF, CCL1, and CCL2 were significantly reduced, with CCL9 also impaired. Notably, gene expression was not impaired for any inflammatory mediator measured. Functionally, this suggests that TAZ is a contributor to mast cell degranulation and inflammatory mediator secretion. Given unimpacted induced gene expression for mediators measured, we propose that TAZ reduction impairs mast cell exocytosis mechanisms. We thus identify a potential new contributor to immunometabolism that enhances our understanding of mast cell signaling metabolic pathway interactions during allergic inflammation.
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Aciltransferasas/metabolismo , Inmunoglobulina E/inmunología , Mediadores de Inflamación/metabolismo , Mastocitos/inmunología , Mastocitos/metabolismo , Aciltransferasas/genética , Alérgenos/inmunología , Animales , Inflamación/inmunología , Inflamación/metabolismo , Ratones , ARN Interferente Pequeño/genética , Receptores de IgE/metabolismo , Transducción de SeñalRESUMEN
Skeletal muscle, a highly active tissue, makes up 40% of the total body weight. This tissue relies on mitochondria for ATP production, calcium homeostasis, and programed cell death. Mitochondrial phospholipid composition, namely, cardiolipin (CL), influences the functional efficiency of mitochondrial proteins, specifically cytochrome c. The interaction of CL with cytochrome c in the presence of free radicals induces structural and functional changes promoting peroxidase activity and cytochrome c release, a key event in the initiation of apoptosis. The CL acyl chain degree of saturation has been implicated in the cytochrome c to cytochrome c peroxidase transition in liposomal models. However, mitochondrial membranes are composed of differing CL acyl chain composition. Currently, it is unclear how differing CL acyl chain composition utilizing liposomes will influence the cytochrome c form and function as a peroxidase. Thus, this study examined the role of CL acyl chain saturation within liposomes broadly reflecting the relative CL composition of mitochondrial membranes from healthy and dystrophic mouse muscle on cytochrome c conformation and function. Despite no differences in protein conformation or function between healthy and dystrophic liposomes, cytochrome c's affinity to CL increased with greater unsaturation. These findings suggest that increasing CL acyl chain saturation, as implicated in muscle wasting diseases, may not influence cytochrome c transformation and function as a peroxidase but may alter its interaction with CL, potentially impacting further downstream effects.
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Cardiolipinas/metabolismo , Citocromos c/metabolismo , Peroxidasas/metabolismo , Conformación Proteica , Animales , Antioxidantes/farmacología , Liposomas/metabolismo , Ratones , Mitocondrias/metabolismo , Peroxidasas/farmacología , Fosfolípidos/metabolismo , Conformación Proteica/efectos de los fármacosRESUMEN
OBJECTIVE: This study aimed to explore the individual and combined effects of skim milk powder (SMP) and exercise on indices of systemic and liver lipid metabolism in male obese rats. METHODS: Rats were fed a high-fat (~ 40% kcal from fat), high-sugar diet for 8 weeks. At 12 weeks of age, rats were assigned to one of four weight-matched, isocaloric, high-fat, high-sugar groups for 6 weeks: (1) casein-sedentary, (2) casein-exercise, (3) SMP-sedentary, and (4) SMP-exercise. Nonfat SMP or casein was the sole protein source in the dairy and control casein diets, respectively. Exercise training occurred 5 d/wk for 60 minutes on a motorized treadmill. Whole-body metabolism was assessed by a Comprehensive Lab Animal Monitoring System. Lipidomics, Western blot, and polymerase chain reaction were used to assess markers of hepatic lipid metabolism. RESULTS: Exercise, but not SMP, altered the fatty acid composition of liver triglycerides, reduced indices of lipogenesis, and increased expression of genes linked to oxidative metabolism, in conjunction with increases in whole-body fat oxidation. SMP and exercise reduced plasma triglycerides in an additive manner. CONCLUSIONS: These findings provide evidence that SMP and exercise exert distinct effects on whole-body and hepatic carbohydrate and lipid metabolism and that they could work in a synergistic manner to reduce serum triglyceride concentrations.
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Productos Lácteos/normas , Lipogénesis/fisiología , Hígado/fisiopatología , Leche/química , Obesidad/etiología , Condicionamiento Físico Animal/métodos , Animales , Metabolismo de los Lípidos , Lípidos/sangre , Masculino , RatasRESUMEN
Post-menopausal women with heart failure (HF) frequently exhibit cardiogenic dementia. Using a pre-clinical swine model of post-menopausal HF, we recently demonstrated that experimental menopause (ovariectomy; OVX) and HF (6-month cardiac pressure overload/aortic banding; AB) independently altered cerebral vasomotor control and together impaired cognitive function. The purpose of this study was to examine the prefrontal cortex and hippocampus tissues from these animals to assess whether OVX and HF are associated with neurologic alterations that may contribute to cardiogenic dementia. We hypothesized that OVX and HF would independently alter neuronal cell signaling in swine with post-menopausal cardiogenic dementia. Immunoblot analyses revealed OVX was associated with reduced estrogen receptor-α in both brain regions and HF tended to exacerbate OVX-induced deficits in the hippocampus. Further, OVX was associated with a reduction in the ratio of phosphorylated:total Akt and ERK in the hippocampus as well as decreased total Akt and synaptophysin in the prefrontal cortex. In contrast, HF was associated with a trend toward reduced phosphorylated:total ERK in the prefrontal cortex. In addition, HF was associated with decreased ß-amyloid (1-38) in the prefrontal cortex and increased ß-amyloid (1-38) in the hippocampus. Regional brain lipid analysis revealed OVX tended to increase total, saturated, and monounsaturated fatty acid content in the prefrontal cortex, with the greatest magnitude of change occurring in the AB-OVX group. The data from this study suggest that OVX and HF are independently associated with regional-specific neurologic changes in the brain that contribute to the cardiogenic dementia profile in this model. This pre-clinical swine model may be a useful tool for better understanding post-menopausal cardiogenic dementia pathology and developing novel therapies.
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Calcineurin is a Ca2+/calmodulin (CaM)-dependent phosphatase that plays a critical role in promoting the slow fiber phenotype and myoblast fusion in skeletal muscle, thereby making calcineurin an attractive cellular target for enhancing fatigue resistance, muscle metabolism, and muscle repair. Neurogranin (Ng) is a CaM-binding protein thought to be expressed solely in brain and neurons, where it inhibits calcineurin signaling by sequestering CaM, thus lowering its cellular availability. Here, we demonstrate for the first time the expression of Ng protein and mRNA in mammalian skeletal muscle. Both protein and mRNA levels are greater in slow-oxidative compared with fast-glycolytic muscles. Coimmunoprecipitation of CaM with Ng in homogenates of C2C12 myotubes, mouse soleus, and human vastus lateralis suggests that these proteins physically interact. To determine whether Ng inhibits calcineurin signaling in muscle, we used Ng siRNA with C2C12 myotubes to reduce Ng protein levels by 60%. As a result of reduced Ng expression, C2C12 myotubes had enhanced CaM-calcineurin binding and calcineurin signaling as indicated by reduced phosphorylation of nuclear factor of activated T cells and increased utrophin mRNA. In addition, calcineurin signaling affects the expression of myogenin and stabilin-2, which are involved in myogenic differentiation and myoblast fusion, respectively. Here, we found that both myogenin and stabilin-2 were significantly elevated by Ng siRNA in C2C12 cells, concomitantly with an increased fusion index. Taken together, these results demonstrate the expression of Ng in mammalian skeletal muscle where it appears to be a novel regulator of calcineurin signaling.
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Calcineurina/biosíntesis , Músculo Esquelético/metabolismo , Mioblastos/metabolismo , Neurogranina/biosíntesis , Transducción de Señal/fisiología , Animales , Calcineurina/genética , Expresión Génica , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Músculo Esquelético/citología , Neurogranina/genética , Adulto JovenRESUMEN
The relationship between liver interleukin-6 (IL-6) resistance following high-fat diet (HFD)-induced obesity and glucose intolerance is unclear. The purpose of this study was to assess the temporal development of hepatic IL-6 resistance and the role of endoplasmic reticulum (ER) stress in this process. We hypothesized that HFD would rapidly induce hepatic IL-6 resistance through a mechanism involving ER stress. Male C57BL/6N mice consumed chow or a HFD (60%) derived from lard (saturated) or olive oil (monounsaturated) for 4 days or 7 weeks before being injected intraperitoneally with IL-6 (6 ng·kg-1). Glucose, insulin, and pyruvate tolerance tests were used as proxies for systemic glucose metabolism and hepatic glucose production, respectively. Primary mouse hepatocytes were incubated with palmitate (saturated) and oleate (unsaturated) overnight, then treated with 20 ng/ml IL-6. ER stress was induced via tunicamycin or prevented by sodium phenylbutyrate (PBA). Seven weeks of a saturated, but not monounsaturated, HFD reduced hepatic IL-6 signaling in conjunction with hepatic ER stress. Palmitate directly impaired IL-6 signaling in hepatocytes along with inducing ER stress. Pharmacologically induced ER stress caused hepatic IL-6 resistance, whereas PBA reversed HFD-induced IL-6 resistance. Chronic HFD-induced obesity is associated with hepatic IL-6 resistance due to saturated FA-induced ER stress.
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Dieta Alta en Grasa/efectos adversos , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Interleucina-6/farmacología , Hígado/metabolismo , Obesidad/inducido químicamente , Obesidad/metabolismo , Animales , Grasas de la Dieta/efectos adversos , Estrés del Retículo Endoplásmico , Glucosa/metabolismo , Intolerancia a la Glucosa/metabolismo , Insulina/metabolismo , Resistencia a la Insulina/fisiología , Hígado/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Fenilbutiratos/farmacología , Transducción de Señal/efectos de los fármacos , Tunicamicina/farmacologíaRESUMEN
Tafazzin (TAZ) is a mitochondrial transacylase that remodels the mitochondrial cardiolipin into its mature form. Through a CRISPR screen, we identified TAZ as necessary for the growth and viability of acute myeloid leukemia (AML) cells. Genetic inhibition of TAZ reduced stemness and increased differentiation of AML cells both in vitro and in vivo. In contrast, knockdown of TAZ did not impair normal hematopoiesis under basal conditions. Mechanistically, inhibition of TAZ decreased levels of cardiolipin but also altered global levels of intracellular phospholipids, including phosphatidylserine, which controlled AML stemness and differentiation by modulating toll-like receptor (TLR) signaling.
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Leucemia Mieloide Aguda/metabolismo , Mitocondrias/enzimología , Fosfolípidos/metabolismo , Factores de Transcripción/metabolismo , Aciltransferasas , Animales , Línea Celular Tumoral , Doxorrubicina/farmacología , Femenino , Humanos , Leucemia Mieloide Aguda/patología , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Ratones Transgénicos , Transducción de Señal/efectos de los fármacos , Receptores Toll-Like/metabolismo , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/deficienciaRESUMEN
Although molecular approaches altering mitochondrial content have implied a direct relationship between mitochondrial bioenergetics and insulin sensitivity, paradoxically, consumption of a high-fat (HF) diet increases mitochondrial content while inducing insulin resistance. We hypothesized that despite the induction of mitochondrial biogenesis, consumption of an HF diet would impair mitochondrial ADP sensitivity in skeletal muscle of mice and therefore manifest in mitochondrial dysfunction in the presence of ADP concentrations indicative of skeletal muscle biology. We found that HF consumption increased mitochondrial protein expression; however, absolute mitochondrial respiration and ADP sensitivity were impaired across a range of biologically relevant ADP concentrations. In addition, HF consumption attenuated the ability of ADP to suppress mitochondrial H2O2 emission, further suggesting impairments in ADP sensitivity. The abundance of ADP transport proteins were not altered, but the sensitivity to carboxyatractyloside-mediated inhibition was attenuated after HF consumption, implicating alterations in adenine nucleotide translocase (ANT) ADP sensitivity in these observations. Moreover, palmitoyl-CoA is known to inhibit ANT, and modeling intramuscular palmitoyl-CoA concentrations that occur after HF consumption exacerbated the deficiency in ADP sensitivity. Altogether, these data suggest that an HF diet induces mitochondrial dysfunction secondary to an intrinsic impairment in mitochondrial ADP sensitivity that is magnified by palmitoyl-CoA.
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Adenosina Difosfato/metabolismo , Intolerancia a la Glucosa/metabolismo , Resistencia a la Insulina/fisiología , Mitocondrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Animales , Dieta Alta en Grasa , Masculino , Ratones , Proteínas Mitocondriales/metabolismo , Consumo de Oxígeno/fisiologíaRESUMEN
BACKGROUND: An increase in phosphatidylcholine:phosphatidylethanolamine (PC:PE) and a decrease in fatty acyl chain length, monounsaturated:polyunsaturated (MUFA:PUFA) fatty acyl ratio reduces SERCA activity in liposomes and in mouse models of obesity and muscular dystrophy. We have previously shown that maximal SERCA activity is significantly reduced in mechanically overloaded (OVL) plantaris, however, whether changes in PC:PE ratio or fatty acyl composition may contribute to the alterations in maximal SERCA activity remain unknown. Here, we tested the hypotheses that in OVL plantaris 1) PC:PE ratio would negatively correlate with maximal SERCA activity and 2) PC fatty acyl chain length (ACL) and/or MUFA:PUFA ratio would positively correlate with maximal SERCA activity. METHODS: To overload plantaris in mice, we transected the soleus and gastrocnemius tendons from one leg, while the contralateral leg underwent a sham surgery. After two weeks, plantaris muscles were extracted, homogenized and processed for SERCA activity and lipid analyses. Specifically, we performed HPTLC densitometry to examine changes in PC, PE, and the ratio of PC:PE. We also performed gas chromatography to assess any potential changes to fatty acyl composition. RESULTS: SERCA activity was significantly reduced in OVL plantaris compared with sham. Coinciding with this, we found a significant increase in PC but not PE in OVL plantaris. In turn, there was an increase in PC:PE but did not reach significance (p = 0.09). However, we found a significant negative correlation between PC:PE and maximal SERCA activity. Fatty acyl composition of PE remained similar between OLV and sham and PC demonstrated higher percent mole fraction of 17:1, 18:1, and ACL compared to sham. In addition, PC ACL, % MUFA, % PUFA, or MUFA:PUFA did not significantly correlate with maximal SERCA activity. CONCLUSIONS: Our results indicate that the phospholipid headgroup PC:PE negatively correlated and could potentially contribute to reductions in SERCA activity seen in functionally overloaded plantaris. In contrast, fatty acyl chain (ACL, % MUFA, % PUFA, MUFA:PUFA) did not correlate with maximal SERCA activity. Future studies will determine whether altering PC:PE with genetic and dietary interventions can influence SERCA activity and ultimately change the physiological outcome in response to muscle overloading.
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Fosfatidilcolinas/metabolismo , Fosfatidiletanolaminas/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Animales , Ácidos Grasos Omega-3/metabolismo , Ratones , Músculo Esquelético/metabolismo , Fosfatidilcolinas/química , Fosfatidiletanolaminas/química , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/químicaRESUMEN
Impaired microvascular insulin signaling may develop before overt indices of microvascular endothelial dysfunction and represent an early pathological feature of adolescent obesity. Using a translational porcine model of juvenile obesity, we tested the hypotheses that in the early stages of obesity development, impaired insulin signaling manifests in skeletal muscle (triceps), brain (prefrontal cortex), and corresponding vasculatures, and that depressed insulin-induced vasodilation is reversible with acute inhibition of protein kinase Cß (PKCß). Juvenile Ossabaw miniature swine (3.5 mo of age) were divided into two groups: lean control ( n = 6) and obese ( n = 6). Obesity was induced by feeding the animals a high-fat/high-fructose corn syrup/high-cholesterol diet for 10 wk. Juvenile obesity was characterized by excess body mass, hyperglycemia, physical inactivity (accelerometer), and marked lipid accumulation in the skeletal muscle, with no evidence of overt atherosclerotic lesions in athero-prone regions, such as the abdominal aorta. Endothelium-dependent (bradykinin) and -independent (sodium nitroprusside) vasomotor responses in the brachial and carotid arteries (wire myography), as well as in the skeletal muscle resistance and 2A pial arterioles (pressure myography) were unaltered, but insulin-induced microvascular vasodilation was impaired in the obese group. Blunted insulin-stimulated vasodilation, which was reversed with acute PKCß inhibition (LY333-531), occurred alongside decreased tissue perfusion, as well as reduced insulin-stimulated Akt signaling in the prefrontal cortex, but not the triceps. In the early stages of juvenile obesity development, the microvasculature and prefrontal cortex exhibit impaired insulin signaling. Such adaptations may underscore vascular and neurological derangements associated with juvenile obesity.
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Resistencia a la Insulina , Insulina/sangre , Microvasos/metabolismo , Músculo Esquelético/irrigación sanguínea , Obesidad Infantil/metabolismo , Corteza Prefrontal/irrigación sanguínea , Vasodilatación , Factores de Edad , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Masculino , Microvasos/efectos de los fármacos , Microvasos/fisiopatología , Obesidad Infantil/fisiopatología , Fosforilación , Proteína Quinasa C beta/antagonistas & inhibidores , Proteína Quinasa C beta/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal , Porcinos , Porcinos Enanos , Factores de Tiempo , Vasodilatación/efectos de los fármacosRESUMEN
Maternal exposure to hesperidin (HSP) and naringin (NAR) during pregnancy and lactation transiently compromised bone mineral density (BMD) and bone structure at the proximal tibia in female CD-1 offspring. We examined whether maternal consumption of HSP + NAR during pregnancy and lactation compromises BMD, bone structure, and bone strength in male CD-1 offspring. Male CD-1 offspring, from mothers fed a control diet (CON, n = 10) or a 0.5% HSP + 0.25% NAR diet (HSP + NAR, n = 8) for 5 weeks before mating and throughout pregnancy and lactation, were weaned and fed CON until 6 months of age. In vivo micro-computed tomography (µCT) measured tibia BMD and structure at 2, 4, and 6 months of age. Ex vivo µCT measured femur and lumbar vertebrae (LV) structure at age 6 months. Ex vivo BMD (femur, LV) and biomechanical strength (femur and tibia midpoint, femur neck) were assessed at age 6 months by dual energy x-ray absorptiometry and strength testing, respectively. At all ages, HSP + NAR offspring had greater (p < 0.05) proximal tibia cortical structure compared to CON offspring. At age 4 months, proximal tibia trabecular structure was greater (p < 0.05) than CON offspring. At age 6 months, femur neck and LV trabecular structure were greater (p < 0.05) than CON offspring. Our results demonstrate that unlike our previous study of female offspring, maternal consumption of HSP + NAR resulted in greater bone structure at the proximal tibia in male CD-1 offspring that persisted to 6 months of age. Thus, maternal programming of offspring BMD and bone structure from consumption of HSP + NAR occurred as a sex-specific response.
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Densidad Ósea/fisiología , Citrus/metabolismo , Flavanonas/metabolismo , Lactancia/fisiología , Vértebras Lumbares/metabolismo , Animales , Peso Corporal/fisiología , Dieta/efectos adversos , Femenino , Masculino , Ratones , Factores Sexuales , Microtomografía por Rayos X/métodosRESUMEN
Lithium in tap water was previously found to have life-extending effects across 18 Japanese municipalities. Using a larger dataset with several Texas counties, our study shows that lithium concentrations in tap water are negatively associated with all-cause mortality (r = -0.18, p = 0.006, 232 counties) and years of potential life lost (r = -0.22, p = 0.001, 214 counties). Thus, our present findings extend and reinforce lithium's purported life-prolonging effect in humans.
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Agua Potable/química , Litio/análisis , Longevidad , Mortalidad Prematura , Oligoelementos/análisis , Abastecimiento de Agua , Adulto , Anciano , Causas de Muerte , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores Protectores , Factores de Riesgo , Factores Socioeconómicos , Suicidio , Texas/epidemiología , Factores de TiempoRESUMEN
BACKGROUND: Alzheimer's disease (AD) mortality rates have steadily increased over time. Lithium, the current gold standard treatment for bipolar disorder, can exert neuroprotective effects against AD. OBJECTIVE: We examined the relationship between trace levels of lithium in drinking water and changes in AD mortality across several Texas counties. METHODS: 6,180 water samples from public wells since 2007 were obtained and averaged for 234 of 254 Texas counties. Changes in AD mortality rates were calculated by subtracting aggregated age-adjusted mortality rates obtained between 2000-2006 from those obtained between 2009-2015. Using aggregated rates maximized the number of counties with reliable mortality data. Correlational analyses between average lithium concentrations and changes in AD mortality were performed while also adjusting for gender, race, education, rural living, air pollution, physical inactivity, obesity, and type 2 diabetes. RESULTS: Age-adjusted AD mortality rate was significantly increased over time (+27%, pâ<â0.001). Changes in AD mortality were negatively correlated with trace lithium levels (pâ=â0.01, râ=â-0.20), and statistical significance was maintained after controlling for most risk factors except for physical inactivity, obesity, and type 2 diabetes. Furthermore, the prevalence of obesity and type 2 diabetes positively correlated with changes in AD mortality (pâ=â0.01 and 0.03, respectively), but also negatively correlated with trace lithium in drinking water (pâ=â0.05 andâ<0.0001, respectively). CONCLUSION: Trace lithium in water is negatively linked with changes in AD mortality, as well as obesity and type 2 diabetes, which are important risk factors for AD.
Asunto(s)
Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/mortalidad , Agua Potable/efectos adversos , Agua Potable/química , Litio/análisis , Adulto , Factores de Edad , Enfermedad de Alzheimer/etiología , Femenino , Humanos , Estudios Longitudinales , Masculino , Obesidad/epidemiología , Prevalencia , Factores de Riesgo , Estadística como Asunto , Texas/epidemiología , Adulto JovenRESUMEN
OBJECTIVE: To compare the individual and combined effects of dairy and endurance exercise training in reducing weight gain and adiposity in a rodent model of diet-induced obesity. METHODS: An 8-week feeding intervention of a high-fat, high-sugar diet was used to induce obesity in male Sprague-Dawley rats. Rats were then assigned to one of four groups for 6 weeks: (1) casein sedentary (casein-S), (2) casein exercise (casein-E), (3) dairy sedentary (dairy-S), and (4) dairy exercise (dairy-E). Rats were exercise trained by treadmill running 5 d/wk. RESULTS: Dairy-E prevented weight gain to a greater extent than either dairy or exercise alone. Adipose tissue and liver mass were reduced to a similar extent in dairy-S, casein-E, and dairy-E groups. Differences in weight gain were not explained by food intake or total energy expenditure. The total amount of lipid excreted was greater in the dairy-S compared to casein-S and dairy-E groups. CONCLUSIONS: This study provides evidence that dairy limits weight gain to a similar extent as exercise training and the combined effects are greater than either intervention alone. While exercise training reduces weight gain through increases in energy expenditure, dairy appears to increase lipid excretion in the feces.