25 research outputs found
Facteurs mécaniques de la performance lors de la phase d'accélération en BMX chez des pilotes entraînés
No full textCoordinated modulations of markers of energy metabolism and contractile apparatus in rat hind limb muscles following physiological activity changes
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A Deoxyribonucleic Acid Decoy Trapping DUX4 for the Treatment of Facioscapulohumeral Muscular Dystrophy
No full textFacioscapulohumeral dystrophy (FSHD) is characterized by a loss of repressive epigenetic marks leading to the aberrant expression of the DUX4 transcription factor. In muscle, DUX4 acts as a poison protein though the induction of multiple downstream genes. So far, there is no therapeutic solution for FSHD. Because DUX4 is a transcription factor, we developed an original therapeutic approach, based on a DNA decoy trapping the DUX4 protein, preventing its binding to genomic DNA and thereby blocking the aberrant activation of DUX4’s transcriptional network. In vitro, transfection of a DUX4 decoy into FSHD myotubes reduced the expression of the DUX4 network genes. In vivo, both double-stand DNA DUX4 decoys and adeno-associated viruses (AAVs) carrying DUX4 binding sites reduced transcriptional activation of genes downstream of DUX4 in a DUX4-expressing mouse model. Our study demonstrates, both in vitro and in vivo, the feasibility of the decoy strategy and opens new avenues of research
Hedging global environment risks: An option based portfolio insurance
No full textThis paper introduces a financial hedging model for global environment risks. Our approach is based on portfolio insurance under hedging constraints. Investors are assumed to maximize their expected utilities defined on financial and environmental asset values. The optimal investment is determined for quite general utility functions and hedging constraints. In particular, our results suggest how to introduce derivative assets written on the environmental asset.utility maximization, hedging, environmental asset, martingale theory
Publisher Correction: Necroptosis Mediates Myofibre Death in Dystrophin-deficient Mice
No full textThe original version of this article contained an error in Fig. 3. In panel c, the labels 'mdx' and 'mdx Ripk3-/-' were inadvertently inverted. This has now been corrected in the PDF and HTML versions of the Article
A novel laser-doppler flowmetry assisted murine model of acute hindlimb ischemia-reperfusion for free flap research
No full textSuitable and reproducible experimental models of translational research in reconstructive surgery that allow in-vivo investigation of diverse molecular and cellular mechanisms are still limited. To this end we created a novel murine model of acute hindlimb ischemia-reperfusion to mimic a microsurgical free flap procedure. Thirty-six C57BL6 mice (n = 6/group) were assigned to one control and five experimental groups (subject to 6, 12, 96, 120 hours and 14 days of reperfusion, respectively) following 4 hours of complete hindlimb ischemia. Ischemia and reperfusion were monitored using Laser-Doppler Flowmetry. Hindlimb tissue components (skin and muscle) were investigated using histopathology, quantitative immunohistochemistry and immunofluorescence. Despite massive initial tissue damage induced by ischemia-reperfusion injury, the structure of the skin component was restored after 96 hours. During the same time, muscle cells were replaced by young myotubes. In addition, initial neuromuscular dysfunction, edema and swelling resolved by day 4. After two weeks, no functional or neuromuscular deficits were detectable. Furthermore, upregulation of VEGF and tissue infiltration with CD34-positive stem cells led to new capillary formation, which peaked with significantly higher values after two weeks. These data indicate that our model is suitable to investigate cellular and molecular tissue alterations from ischemia-reperfusion such as occur during free flap procedures
AAV-shDUX4 provides short-term benefits but limited long-term efficacy in a DUX4 mouse model of FSHD
No full textInternational audienceThe aberrant expression of the toxic transcription factor DUX4 in skeletal muscle is a hallmark of facioscapulohumeral muscular dystrophy. Effective therapeutic strategies will likely require the inhibition of DUX4, with adeno-associated virus (AAV)-mediated therapies being among the promising approaches. However, the regenerative nature of muscle tissue can impact the long-term efficacy of AAV transduction, leading to reduced transgene persistence and diminishing the sustainability of gene inhibition over time. In this study, we utilized an AAV vector carrying a short hairpin RNA targeting DUX4 (shDUX4) to suppress DUX4 expression in the ACTA1-MCM; FLExDUX4/+ mouse model, which exhibits progressive muscular dystrophy. One month following AAV administration, the treatment significantly mitigated the DUX4-associated pathological features, including molecular, histopathological, and functional force-velocity-endurance (FoVE) parameters. However, by 10 months post-treatment, the therapeutic effects had substantially diminished, with most pathological markers remaining uncorrected and no sustained improvement in muscle force. This decline in therapeutic effect was associated with reduced DUX4 knockdown and a concurrent loss of AAV genomes. These findings highlight that althoughAAV-mediated gene therapy holds significant promise for FSHD treatment, challenges such as muscle fiber turnover and AAV genome dilution must be overcome to achieve sustained therapeutic benefit
Genetic inactivation of acetylcholinesterase causes functional and structural impairment of mouse soleus muscles
No full textInternational audienceAcetylcholinesterase (AChE) plays an essential role in neuromuscular transmission. Not surprisingly, neuromuscular transmission during repetitive nerve stimulation is severely depressed in the AChE knockout mouse (KO). However, whether this deficit in AChE leads to skeletal muscle changes is not known. We have studied the in vitro contractile properties of the postural and locomotor soleus muscles of adult KO and normal (wildtype, WT) mice, and this was completed by histological and biochemical analyses. Our results show that muscle weight, crosssectional area of muscle fibres and absolute maximal isometric force are all reduced in KO mice compared with WT mice. Of interest, the relative amount of slow myosin heavy chain (MHC-1) in muscle homogenates and the percentage of muscle fibres expressing MHC-1 are decreased in the KO mice. Surprisingly, AChE ablation does not modify twitch kinetics, absolute maximal power, fatigue resistance or citrate synthase activity, despite the reduced number of slow muscle fibres. Thus, a deficit in AChE leads to alterations in the structure and function of muscles but these changes are not simply related to the reduced body weight of KO mice. Our results also suggest that this murine model of congenital myasthenic syndrome with endplate AChE deficiency combines alterations in both neurotransmission and intrinsic muscle properties
