204 research outputs found

    Genetic Regulation of Intrinsic Endurance Exercise Capacity in Mice

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    Endurance exercise capacity is a powerful predictor of health status. Having low levels of endurance exercise capacity has been linked with cardiovascular disease. Variation in endurance exercise capacity, measured during a graded exercise test, has been reported across cross-section, twin, and family studies. This variation is evidence of a genetic component to the phenotype of endurance exercise capacity: however, the genetic factors responsible for explaining this variation are undefined, in part because previous research has been performed on a limited scale. Therefore, three sets of experiments were designed to identify: 1) Novel quantitative trait loci (QTL) for endurance exercise capacity in 34 strains of inbred mice using genome-wide association mapping. 2) The effect of chromosome substitution on endurance exercise capacity using linkage analysis in F2 mice. 3) The effect of chromosome substitution on endurance exercise capacity using wild-derived mice. The main findings of this dissertation are: 1) There are strain-specific differences in endurance exercise capacity across 34 strains of male inbred mice. Genome-wide association mapping identified novel putative QTL on chromosomes 2, 7, 11, and 13. 2) Linkage analysis identified a novel QTL on chromosome 14 at the 56 cM position for run time and work. Linkage analysis also identified a potential sex-specific QTL, with the identified QTL significant for male mice only. 3) Novel putative QTL were identified on chromosomes 3 and 14 in chromosome substitution mice from wild-derived mice. These data suggest that chromosome 14 is an important contributor to the genetic regulation of intrinsic endurance exercise capacity. These studies support a genetic component to endurance exercise capacity by identifying strain-specific differences and novel, putative QTL

    Exercise Attenuates CTGF Levels, Delaying the Onset of Fibrosis in the Aging Left Ventricle

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    Aging is associated with a progressive increase in collagen (i.e., fibrosis) in the aging heart. Fibrosis is associated with a stiffening of the heart and a decrease in heart function. Previous data (Kwak, 2008) showed that matrix metalloproteinase (MMP) activity in the aging heart is decreased linked to an elevation TIMP-1 (tissue inhibitor of MMPs-1); while exercise training increased TIMP-1 and reduced MMP expression. Connective tissue growth factor (CTGF) is an upstream inhibitor of TIMP-1 and is implicated in diabetes and heart failure. We hypothesized that exercise would decrease CTGF levels, thus reducing fibrosis in the aged left ventricle. Young (3 months) and old (31 months) male Fischer 344 Ă— Brown Norway F1 hybrid (F344BNF1) rats were used for the study. The rats were randomly assigned to one of the following experimental groups (n=10/group): young sedentary controls (YS), young exercise trained (YE), old sedentary controls (OS), and old exercise trained (OE). Rats walked quickly on a motor-driven treadmill for 45 min/day, 5 days/wk, for 12 wks. Heart levels of CTGF were determined via Immunohistochemistry (IHC). CTGF was expressed more in the old group compared to the young group, as well as the sedentary group compared to the exercise group. Future studies will determine if CTGF is downstream of angiotensin II, TGF-beta, and oxidative stress in regulating MMPs and TIMP-1

    The effects of exercise on caspase-independent mitochondrial proteins in regards to age-related apoptosis

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    Exercise may have protective factors in reducing oxidative stress, mitochondrial dysfunction and mitochondrial caspase-dependent apoptosis with aging. It is presently unclear whether the caspase-independent apoptosis via EndonucleaseG (EndoG) and Apoptosis Inducing Factor (AIF) translocation from the mitochondria to the nucleosome is effected by exercise in aging skeletal muscle. It is understood that in aging skeletal muscle EndoG and AIF do translocate from the mitochondria to the nucleosome. We hypothesize that exercise will attenuate the translocation of EndoG and AIF from the mitochondria to the nucleosome in aging white gastrocnemius muscle. Twenty-four Fischer Brown Norway rats were randomly assigned to four groups, young sedentary, old sedentary, young exercisers and old exercisers. The exercise consisted of treadmill training. The protein expression of EndoG and AIF were analyzed using western blot assays. In the old sedentary group, EndoG increased 86.4 % in the soluble fraction, but there was no change in the young groups. EndoG protein levels in the nucleosome fraction of young exercisers decreased 49 % when compared to young sedentary controls and old sedentary increased by 86.5 % when compared to young sedentary controls. With AIF changes in the soluble fraction were neglible. Protein levels of AIF in the nucleosome fraction increased 64 % in the old sedentary group compared to young sedentary controls. The data indicates that exercise was a protective factor against caspase-independent apoptosis by decreasing the translocation of EndoG and AIF to the nucleosome in aged skeletal muscle

    Laser Light Sheet Flow Visualization of the Space Launch System Booster Separation Test

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    Planar flow visualizations were obtained in a wind tunnel test in the NASA Langley Research Centers Unitary Plan Wind Tunnel using the laser-light-sheet method. This method uses a laser to illuminate fine particles generated in the wind tunnel to visualize flow structures. The test article was designed to simulate the separation of the two solid rocket boosters (SRBs) from the core stage of the NASA Space Launch System (SLS) at Mach 4 using a scale model. The test was run on of the SLS Block 1B Cargo (27005) configuration and the SLS Block 1B Crew (28005) configuration. Planar flow visualization was obtained only on the crew configuration. Air at pressures up to 1500 psi was used to simulate plumes from the booster separation motors (BSMs) located at the nose, and aft skirt of the two boosters. The facility free stream was seeded with water vapor, which condensed and froze into small ice crystals in the tunnel nozzle expansion. A continuous wave green (532 nm) laser sheet was used to illuminate the ice crystals, and the resulting Mie-scattered light was collected with a camera. The resulting images clearly identify shock waves and other flow features including BSM plume shapes. Measurements were acquired for different BSM pressures and booster separation locations

    Reactive stress-coping styles show more variable reproductive expenditure and fitness outcomes

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    Stress-coping styles dictate how individuals react to stimuli and can be measured by the integrative physiological parameter of resting heart-rate variability (HRV); low resting HRV indicating proactive coping styles, while high resting HRV typifies reactive individuals. Over 5 successive breeding seasons we measured resting HRV of 57 lactating grey seals. Mothers showed consistent individual differences in resting HRV across years. We asked whether proactive and reactive mothers differed in their patterns of maternal expenditure and short-term fitness outcomes within seasons, using maternal daily mass loss rate to indicate expenditure, and pup daily mass gain to indicate within season fitness outcomes. We found no difference in average rates of maternal daily mass loss or pup daily mass gain between proactive and reactive mothers. However, reactive mothers deviated more from the sample mean for maternal daily mass and pup daily mass gain than proactive mothers. Thus, while proactive mothers exhibit average expenditure strategies with average outcomes, expenditure varies much more among reactive mothers with more variable outcomes. Overall, however, mean fitness was equal across coping styles, providing a mechanism for maintaining coping style diversity within populations. Variability in reactive mothers’ expenditures and success is likely a product of their attempts to match phenotype to prevailing environmental conditions, achieved with varying degrees of success

    The Effects of Acute Beetroot Juice Ingestion on Exercise and Cognitive Performance in Female Athletes

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    Nitrate-rich beetroot juice can enhance intense exercise performance which is attributed to enhanced skeletal muscle contractility. However, limited data exist in females and it is unknown whether dietary nitrate has an ergogenic effect in this population. PURPOSE: To investigate the potential effects of acute nitrate ingestion on a battery of exercise performance and cognitive tests before and after fatiguing intermittent running exercise. METHODS: Fifteen female team-sport athletes were assigned in a randomized, double-blind, crossover design to consume nitrate-rich beetroot juice (BR; 12 mmol of nitrate) and nitrate-depleted beetroot juice (PL; 0.10 mmol of nitrate) 2.5 h prior to performing the exercise protocol, with a washout period of 7 days between trials. Running 10 m and 20 m sprint split times, sprint reaction time, upper- and lower-body power, handgrip strength, and cognitive flexibility were measured before and after the Yo-Yo intermittent recovery level 1 (Yo-Yo IR1) test, during which performance and rate of perceived exertion were recorded. RESULTS: There were no significant differences in any performance outcome or cognitive flexibility (P \u3e 0.05). CONCLUSION: These findings indicate that acute nitrate ingestion does not influence performance in sprints, intermittent running, power, strength, or cognitive function in young adult female team-sport athletes

    Selective Inhibition of p300 HAT Blocks Cell Cycle Progression, Induces Cellular Senescence, and Inhibits the DNA Damage Response in Melanoma Cells

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    Epigenetic events, including covalent post-translational modifications of histones, have been demonstrated to have critical roles in tumor development and progression. The transcriptional coactivator p300/CBP possesses both histone acetyltransferase (HAT) activity and scaffolding properties that directly influence the transcriptional activation of targeted genes. We have used a potent and specific inhibitor of p300/CBP HAT activity, C646, in order to evaluate the functional contributions of p300/CBP HAT to tumor development and progression. Here we report that C646 inhibits the growth of human melanoma and other tumor cells and promotes cellular senescence. Global assessment of the p300 HAT transcriptome in human melanoma identified functional roles in promoting cell cycle progression, chromatin assembly, and activation of DNA repair pathways through direct transcriptional regulatory mechanisms. In addition, C646 is shown to promote sensitivity to DNA damaging agents, leading to the enhanced apoptosis of melanoma cells after combination treatment with cisplatin. Together, our data suggest that p300 HAT activity mediates critical growth regulatory pathways in tumor cells and may serve as a potential therapeutic target for melanoma and other malignancies by promoting cellular responses to DNA damaging agents that are currently ineffective against specific cancers

    RNA-associated autoantigens activate B cells by combined B cell antigen receptor/Toll-like receptor 7 engagement

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    Previous studies (Leadbetter, E.A., I.R. Rifkin, A.H. Hohlbaum, B. Beaudette, M.J. Shlomchik, and A. Marshak-Rothstein. 2002. Nature. 416:603–607; Viglianti, G.A., C.M. Lau, T.M. Hanley, B.A. Miko, M.J. Shlomchik, and A. Marshak-Rothstein. 2003. Immunity. 19:837–847) established the unique capacity of DNA and DNA-associated autoantigens to activate autoreactive B cells via sequential engagement of the B cell antigen receptor (BCR) and Toll-like receptor (TLR) 9. We demonstrate that this two-receptor paradigm can be extended to the BCR/TLR7 activation of autoreactive B cells by RNA and RNA-associated autoantigens. These data implicate TLR recognition of endogenous ligands in the response to both DNA- and RNA-associated autoantigens. Importantly, the response to RNA-associated autoantigens was markedly enhanced by IFN-α, a cytokine strongly linked to disease progression in patients with systemic lupus erythematosus (SLE). As further evidence that TLRs play a key role in autoantibody responses in SLE, we found that autoimmune-prone mice, lacking the TLR adaptor protein MyD88, had markedly reduced chromatin, Sm, and rheumatoid factor autoantibody titers
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