Nrf2 deficiency does not affect denervation‐induced alterations in mitochondrial fission and fusion proteins in skeletal muscle

Oxidative stress-induced mitochondrial dysfunction is associated with age-related and disuse-induced skeletal muscle atrophy. However, the role ofnuclear factor erythroid 2-related factor 2 (Nrf2) during muscle fiber atrophyremains to be elucidated. In this study, we examined whether deficiency ofNrf2, a master regulator of antioxidant transcription, promotes denervation-induced mitochondrial fragmentation and muscle atrophy. We found that theexpression of Nrf2 and its target antioxidant genes was upregulated at 2 weeksafter denervation in wild-type (WT) mice. The response of these antioxidantgenes was attenuated in Nrf2 knockout (KO) mice. Nrf2 KO mice exhibitedelevated levels of 4-hydroxynonenal in the skeletal muscle, whereas the proteinlevels of the mitochondrial oxidative phosphorylation complex IV wasdeclined in the denervated muscle of these mice. Increased in mitochondrialfission regulatory proteins and decreased fusion proteins in response to dener-vation were observed in both WT and KO mice; however, no difference wasobserved between the two groups. These findings suggest that Nrf2 deficiencyaggravates denervation-induced oxidative stress, but does not affect the alter-ations in mitochondrial morphology proteins and the loss of skeletal musclemass

PO-074 Acute effects of lactate administration prior to endurance exercise on intramuscular signaling

Objective High-intensity exercise, which increases blood lactate concentration, is known as an effective method to induce mitochondrial biogenesis compared to traditional endurance exercise. In addition, it has been reported that lactate acts as a signaling molecule inducing mitochondrial biogenesis. Therefore, we hypothesized that efficacy of high-intensity exercise is partly induced by lactate. The purpose of this study was to investigate the effects of lactate administration on signaling related to mitochondrial biogenesis. Methods 8-week-old male ICR mice were used in this study. Mice were intraperitoneally administrated phosphate buffered saline (PBS) or 1 g/kg of body weight of sodium lactate. Immediately after the administration, mice were kept sedentary or performed treadmill exercise (20 m/min) for 60 min. Hence, there are the following four groups in this study: the PBS-sedentary, the Lactate-sedentary, the PBS-exercised and the Lactate-exercised. The blood, and the soleus and the plantaris muscles were harvested immediately after the rest or exercise. Nucleus and mitochondria were isolated to assess the localization of p53. Two-way ANOVA (Lactate x Exercise) was performed for statistical analysis. Results We first measured blood substrates and muscle glycogen concentrations. Lactate administration significantly increased blood lactate and plasma free fatty acid concentrations. Exercise significantly decreased glycogen concentration both in the soleus and the plantaris muscles. Furthermore, lactate administration significantly decreased muscle glycogen concentration only in the soleus muscle. To clarify the effects of lactate administration on intramuscular signaling, we assessed kinases related to mitochondrial biogenesis. Main effect of exercise was observed in phosphorylation state of AMPK, ACC, p38 MAPK, and CaMKII in the soleus and the plantaris muscles. There was a trend of negative effect of lactate in CaMKII phosphorylation in the soleus muscle. However, there was no effect of lactate administration on the other kinases. We also investigated phosphorylation and localization of p53. As a result, lactate administration tended to increase p53 phosphorylation in the plantaris muscle. However, p53 was not translocated to nucleus or mitochondria. Conclusions Lactate administration affected plasma FFA concentration and muscle glycogen concentration. However, acute lactate administration did not dramatically change intracellular signaling assessed in this study.&nbsp

Thermal conductivity in B- and C- phase of UPt_3

Although the superconductivity in UPt_3 is one of the most well studied, there are still lingering questions about the nodal directions in the B and C phase in the presence of a magnetic field. Limiting ourselves to the low temperature regime (T<<Delta(0)), we study the magnetothermal conductivity with in semiclassical approximation using Volovik's approach. The angular dependence of the magnetothermal conductivity for an arbitrary field direction should clarify the nodal structure in UPt_3.Comment: 4 pages, 5 figure

Effects of Nrf2 deficiency on mitochondrial oxidative stress in aged skeletal muscle

Oxidative stress and mitochondrial dysfunction are associated with the aging process. However, the role of nuclear factor erythroid 2 ‐related factor 2 (Nrf2) in skeletal muscle during aging remains to be clarified. In the current study, we assessed whether the lack of Nrf2, which is known as a master regulator of redox homeostasis, promotes age‐related mitochondrial dysfunction and muscle atrophy in skeletal muscle. Here, we demonstrated that mitochondrial 4‐hydroxynonenal and protein carbonyls, markers of oxidative stress, were robustly elevated in aged Nrf2 knockout (KO) mice because of the decreased expression of Nrf2‐target antioxidant genes. Mitochondrial respiration declined with aging; however, there was no difference between Nrf2 KO and age‐matched WT mice. Similarly, cytochrome c oxidase activity was lower in aged WT and Nrf2 KO mice compared with young WT mice. The expression of Mfn1 and Mfn2 mRNA was lower in aged Nrf2 KO muscle. Mitochondrial reactive oxygen species production per oxygen consumed was elevated in aged Nrf2 KO mice. There was no effect of Nrf2 KO on muscle mass normalized to body weight. These results suggest that Nrf2 deficiency exacerbates age‐related mitochondrial oxidative stress but does not affect the decline of respiratory function in skeletal muscle

Branch Mode Selection during Early Lung Development

Many organs of higher organisms, such as the vascular system, lung, kidney, pancreas, liver and glands, are heavily branched structures. The branching process during lung development has been studied in great detail and is remarkably stereotyped. The branched tree is generated by the sequential, non-random use of three geometrically simple modes of branching (domain branching, planar and orthogonal bifurcation). While many regulatory components and local interactions have been defined an integrated understanding of the regulatory network that controls the branching process is lacking. We have developed a deterministic, spatio-temporal differential-equation based model of the core signaling network that governs lung branching morphogenesis. The model focuses on the two key signaling factors that have been identified in experiments, fibroblast growth factor (FGF10) and sonic hedgehog (SHH) as well as the SHH receptor patched (Ptc). We show that the reported biochemical interactions give rise to a Schnakenberg-type Turing patterning mechanisms that allows us to reproduce experimental observations in wildtype and mutant mice. The kinetic parameters as well as the domain shape are based on experimental data where available. The developed model is robust to small absolute and large relative changes in the parameter values. At the same time there is a strong regulatory potential in that the switching between branching modes can be achieved by targeted changes in the parameter values. We note that the sequence of different branching events may also be the result of different growth speeds: fast growth triggers lateral branching while slow growth favours bifurcations in our model. We conclude that the FGF10-SHH-Ptc1 module is sufficient to generate pattern that correspond to the observed branching modesComment: Initially published at PLoS Comput Bio

Critical Josephson Current in a Model Pb/YBa_2Cu_3O_7 Junction

In this article we consider a simple model for a c--axis Pb/YBa_2Cu_3O_{7-\delta} Josephson junction. The observation of a nonzero current in such a junction by Sun et al. [A. G. Sun, D. A. Gajewski, M. B. Maple, R. C. Dynes, Phys. Rev. Lett. 72, 2267 (1994)] has been taken as evidence against d--wave superconductivity in YBa_2Cu_3O_{7-\delta}. We suggest, however, that the pairing interaction in the CuO_2 planes may well be d--wave but that the CuO chains destroy the tetragonal symmetry of the system. We examine two ways in which this happens. In a simple model of an incoherent junction, the chains distort the superconducting condensate away from d_{x^2-y^2} symmetry. In a specular junction the chains destroy the tetragonal symmetry of the tunneling matrix element. In either case, the loss of tetragonal symmetry results in a finite Josephson current. Our calculated values of the critical current for specular junctions are in good agreement with the results of Sun and co-workers.Comment: Latex File, 21 pages, 6 figures in uuencoded postscript, In Press (Phys. Rev. B

Phase separation and suppression of critical dynamics at quantum transitions of itinerant magnets: MnSi and (Sr1−x_{1-x}Cax_{x})RuO3_{3}

Quantum phase transitions (QPTs) have been studied extensively in correlated electron systems. Characterization of magnetism at QPTs has, however, been limited by the volume-integrated feature of neutron and magnetization measurements and by pressure uncertainties in NMR studies using powderized specimens. Overcoming these limitations, we performed muon spin relaxation ($\mu$SR) measurements which have a unique sensitivity to volume fractions of magnetically ordered and paramagnetic regions, and studied QPTs from itinerant heli/ferro magnet to paramagnet in MnSi (single-crystal; varying pressure) and (Sr$_{1-x}$Ca$_{x}$)RuO$_{3}$ (ceramic specimens; varying $x$). Our results provide the first clear evidence that both cases are associated with spontaneous phase separation and suppression of dynamic critical behavior, revealed a slow but dynamic character of the ``partial order'' diffuse spin correlations in MnSi above the critical pressure, and, combined with other known results in heavy-fermion and cuprate systems, suggest a possibility that a majority of QPTs involve first-order transitions and/or phase separation.Comment: 11 pages, 4 figures, 21 authors, to appear in Nature Physic