The effect of activity on the rat skeletal muscle contractile apparatus

In 35 m/min running rats the myosin heavy chains have a faster turnover rate in all three types of skeletal muscle fibers. In the ease of 95 m/min running rats the myosin heavy chains turned over faster only in fast-glyeolytie and fast-oxidative-glycolytie type of muscle fibers. The turnover rate of myosin light chains remained at the control animals’ level. 95 mlmin running exercise caused significant alterations in myosin heavy chain isoforms percentage —the decrease in type I and IIb of myosin heavy chain isoforms and the increase in type lla/d of myosin heavy chain isoforms. At the same time the turnover rate of the total myosin heavy chain fraction showed the inerease.The ratio of myosin heavy chains and actin decreased inglycolytie type of muscle fibers in 95 mlmin running rats

The Combined Impact Of IgLON Family Proteins Lsamp And Neurotrimin On Developing Neurons And Behavioral Profiles In Mouse

Cell surface neural adhesion proteins are critical components in the complex orchestration of cell proliferation, apoptosis, and neuritogenesis essential for proper brain construction and behavior. We focused on the impact of two plasticity-associated IgLON family neural adhesion molecules, Neurotrimin (Ntm) and Limbic system associated membrane protein (Lsamp), on mouse behavior and its underlying neural development. Phenotyping neurons derived from the hippocampi of Lsamp−/−, Ntm−/− and Lsamp−/−Ntm−/− mice was performed in parallel with behavioral testing. While the anatomy of mutant brains revealed no gross changes, the Ntm−/− hippocampal neurons exhibited premature sprouting of neurites and manifested accelerated neurite elongation and branching. We propose that Ntm exerts an inhibitory impact on neurite outgrowth, whereas Lsamp appears to be an enhancer of the said process as premature neuritogenesis in Ntm−/− neurons is apparent only in the presence of Lsamp. We also show interplay between Lsamp and Ntm in regulating tissue homeostasis: the impact of Ntm on cellular proliferation was dependent on Lsamp, and Lsamp appeared to be a positive regulator of apoptosis in the presence of Ntm. Behavioral phenotyping indicated test-specific interactions between Lsamp and Ntm. The phenotypes of single mutant lines, such as reduced swimming speed in Morris water maze and increased activity in the elevated plus maze, were magnified in Lsamp−/−Ntm−/− mice. Altogether, evidence both from behavioral experiments and cultured hippocampal cells show combined and differential interactions between Ntm and Lsamp in the formation of hippocampal circuits and behavioral profiles. We demonstrate that mutual interactions between IgLON molecules regulate the initiation of neurite sprouting at very early ages, and even cell-autonomously, independent of their regulation of cell-cell adhesion

Health impact assessment of particulate pollution in Tallinn using fine spatial resolution and modeling techniques

<p>Abstract</p> <p>Background</p> <p>Health impact assessments (HIA) use information on exposure, baseline mortality/morbidity and exposure-response functions from epidemiological studies in order to quantify the health impacts of existing situations and/or alternative scenarios. The aim of this study was to improve HIA methods for air pollution studies in situations where exposures can be estimated using GIS with high spatial resolution and dispersion modeling approaches.</p> <p>Methods</p> <p>Tallinn was divided into 84 sections according to neighborhoods, with a total population of approx. 390 000 persons. Actual baseline rates for total mortality and hospitalization with cardiovascular and respiratory diagnosis were identified. The exposure to fine particles (PM_2.5) from local emissions was defined as the modeled annual levels. The model validation and morbidity assessment were based on 2006 PM₁₀or PM_2.5levels at 3 monitoring stations. The exposure-response coefficients used were for total mortality 6.2% (95% CI 1.6–11%) per 10 μg/m³increase of annual mean PM_2.5concentration and for the assessment of respiratory and cardiovascular hospitalizations 1.14% (95% CI 0.62–1.67%) and 0.73% (95% CI 0.47–0.93%) per 10 μg/m³increase of PM₁₀. The direct costs related to morbidity were calculated according to hospital treatment expenses in 2005 and the cost of premature deaths using the concept of Value of Life Year (VOLY).</p> <p>Results</p> <p>The annual population-weighted-modeled exposure to locally emitted PM_2.5in Tallinn was 11.6 μg/m³. Our analysis showed that it corresponds to 296 (95% CI 76528) premature deaths resulting in 3859 (95% CI 10236636) Years of Life Lost (YLL) per year. The average decrease in life-expectancy at birth per resident of Tallinn was estimated to be 0.64 (95% CI 0.17–1.10) years. While in the polluted city centre this may reach 1.17 years, in the least polluted neighborhoods it remains between 0.1 and 0.3 years. When dividing the YLL by the number of premature deaths, the decrease in life expectancy among the actual cases is around 13 years. As for the morbidity, the short-term effects of air pollution were estimated to result in an additional 71 (95% CI 43–104) respiratory and 204 (95% CI 131–260) cardiovascular hospitalizations per year. The biggest external costs are related to the long-term effects on mortality: this is on average €150 (95% CI 40–260) million annually. In comparison, the costs of short-term air-pollution driven hospitalizations are small €0.3 (95% CI 0.2–0.4) million.</p> <p>Conclusion</p> <p>Sectioning the city for analysis and using GIS systems can help to improve the accuracy of air pollution health impact estimations, especially in study areas with poor air pollution monitoring data but available dispersion models.</p

β-Hydroxy-β-Methylbutyrate (HMB) Normalizes Dexamethasone-Induced Autophagy-Lysosomal Pathway in Skeletal Muscle

Dexamethasone-induced muscle atrophy is due to an increase in protein breakdown and a decrease in protein synthesis, associated with an over-stimulation of the autophagy-lysosomal pathway. These effects are mediated by alterations in IGF-1 and PI3K/Akt signaling. In this study, we have investigated the effects of β-Hydroxy-β-methylbutyrate (HMB) on the regulation of autophagy and proteosomal systems. Rats were treated during 21 days with dexamethasone as a model of muscle atrophy. Co-administration of HMB attenuated the effects promoted by dexamethasone. HMB ameliorated the loss in body weight, lean mass and the reduction of the muscle fiber cross-sectional area (shrinkage) in gastrocnemius muscle. Consequently, HMB produced an improvement in muscle strength in the dexamethasone-treated rats. To elucidate the molecular mechanisms responsible for these effects, rat L6 myotubes were used. In these cells, HMB significantly attenuated lysosomal proteolysis induced by dexamethasone by normalizing the changes observed in autophagosome formation, LC3 II, p62 and Bnip3 expression after dexamethasone treatment. HMB effects were mediated by an increase in FoxO3a phosphorylation and concomitant decrease in FoxO transcriptional activity. The HMB effect was due to the restoration of Akt signaling diminished by dexamethasone treatment. Moreover, HMB was also involved in the regulation of the activity of ubiquitin and expression of MurF1 and Atrogin-1, components of the proteasome system that are activated or up-regulated by dexamethasone. In conclusion, in vivo and in vitro studies suggest that HMB exerts protective effects against dexamethasone-induced muscle atrophy by normalizing the Akt/FoxO axis that controls autophagy and ubiquitin proteolysis.This project has been funded by Abbott Nutrition R&D

Epileptogenic potential of mefloquine chemoprophylaxis: a pathogenic hypothesis

<p>Abstract</p> <p>Background</p> <p>Mefloquine has historically been considered safe and well-tolerated for long-term malaria chemoprophylaxis, but prescribing it requires careful attention in order to rule out contraindications to its use. Contraindications include a history of certain neurological conditions that might increase the risk of seizure and other adverse events. The precise pathophysiological mechanism by which mefloquine might predispose those with such a history to seizure remains unclear.</p> <p>Presentation of the hypothesis</p> <p>Studies have demonstrated that mefloquine at doses consistent with chemoprophylaxis accumulates at high levels in brain tissue, which results in altered neuronal calcium homeostasis, altered gap-junction functioning, and contributes to neuronal cell death. This paper reviews the scientific evidence associating mefloquine with alterations in neuronal function, and it suggests the novel hypothesis that among those with the prevalent EPM1 mutation, inherited and mefloquine-induced impairments in neuronal physiologic safeguards might increase risk of GABAergic seizure during mefloquine chemoprophylaxis.</p> <p>Testing and implications of the hypothesis</p> <p>Consistent with case reports of tonic-clonic seizures occurring during mefloquine chemoprophylaxis among those with family histories of epilepsy, it is proposed here that a new contraindication to mefloquine use be recognized for people with EPM1 mutation and for those with a personal history of myoclonus or ataxia, or a family history of degenerative neurologic disorder consistent with EPM1. Recommendations and directions for future research are presented.</p

Misfolded SOD1 Associated with Motor Neuron Mitochondria Alters Mitochondrial Shape and Distribution Prior to Clinical Onset

Mutations in superoxide dismutase (SOD1) are causative for inherited amyotrophic lateral sclerosis. A proportion of SOD1 mutant protein is misfolded onto the cytoplasmic face of mitochondria in one or more spinal cord cell types. By construction of mice in which mitochondrially targeted enhanced green fluorescent protein is selectively expressed in motor neurons, we demonstrate that axonal mitochondria of motor neurons are primary in vivo targets for misfolded SOD1. Mutant SOD1 alters axonal mitochondrial morphology and distribution, with dismutase active SOD1 causing mitochondrial clustering at the proximal side of Schmidt-Lanterman incisures within motor axons and dismutase inactive SOD1 producing aberrantly elongated axonal mitochondria beginning pre-symptomatically and increasing in severity as disease progresses. Somal mitochondria are altered by mutant SOD1, with loss of the characteristic cylindrical, networked morphology and its replacement by a less elongated, more spherical shape. These data indicate that mutant SOD1 binding to mitochondria disrupts normal mitochondrial distribution and size homeostasis as early pathogenic features of SOD1 mutant-mediated ALS

Enhancement of Cell Membrane Invaginations, Vesiculation and Uptake of Macromolecules by Protonation of the Cell Surface

The different pathways of endocytosis share an initial step involving local inward curvature of the cell’s lipid bilayer. It has been shown that to generate membrane curvature, proteins or lipids enforce transversal asymmetry of the plasma membrane. Thus it emerges as a general phenomenon that transversal membrane asymmetry is the common required element for the formation of membrane curvature. The present study demonstrates that elevating proton concentration at the cell surface stimulates the formation of membrane invaginations and vesiculation accompanied by efficient uptake of macromolecules (Dextran-FITC, 70 kD), relative to the constitutive one. The insensitivity of proton induced uptake to inhibiting treatments and agents of the known endocytic pathways suggests the entry of macromolecules to proceeds via a yet undefined route. This is in line with the fact that neither ATP depletion, nor the lowering of temperature, abolishes the uptake process. In addition, fusion mechanism such as associated with low pH uptake of toxins and viral proteins can be disregarded by employing the polysaccharide dextran as the uptake molecule. The proton induced uptake increases linearly in the extracellular pH range of 6.5 to 4.5, and possesses a steep increase at the range of 4> pH>3, reaching a plateau at pH≤3. The kinetics of the uptake implies that the induced vesicles release their content to the cytosol and undergo rapid recycling to the plasma membrane. We suggest that protonation of the cell’s surface induces local charge asymmetries across the cell membrane bilayer, inducing inward curvature of the cell membrane and consequent vesiculation and uptake

Bafilomycin A1 activates respiration of neuronal cells via uncoupling associated with flickering depolarization of mitochondria

Bafilomycin A1 (Baf) induces an elevation of cytosolic Ca2+ and acidification in neuronal cells via inhibition of the V-ATPase. Also, Baf uncouples mitochondria in differentiated PC12 (dPC12), dSH-SY5Y cells and cerebellar granule neurons, and markedly elevates their respiration. This respiratory response in dPC12 is accompanied by morphological changes in the mitochondria and decreases the mitochondrial pH, Ca2+ and ΔΨm. The response to Baf is regulated by cytosolic Ca2+ fluxes from the endoplasmic reticulum. Inhibition of permeability transition pore opening increases the depolarizing effect of Baf on the ΔΨm. Baf induces stochastic flickering of the ΔΨm with a period of 20 ± 10 s. Under conditions of suppressed ATP production by glycolysis, oxidative phosphorylation impaired by Baf does not provide cells with sufficient ATP levels. Cells treated with Baf become more susceptible to excitation with KCl. Such mitochondrial uncoupling may play a role in a number of (patho)physiological conditions induced by Baf