20 research outputs found

    Duchenne muscular dystrophy trajectory in R-DMDdel52 preclinical rat model identifies COMP as biomarker of fibrosis

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    International audienceAbstractDuchenne muscular dystrophy (DMD) is a fatal muscle-wasting disorder caused by mutations in the Dystrophin gene and for which there is currently no cure. To bridge the gap between preclinical and therapeutic evaluation studies, we have generated a rat model for DMD that carries an exon 52 deletion (R-DMDdel52) causing a complete lack of dystrophin protein. Here we show that R-DMDdel52 animals recapitulated human DMD pathophysiological trajectory more faithfully than the mdx mouse model. We report that R-DMDdel52 rats displayed progressive and severe skeletal muscle loss associated with fibrotic deposition, fat infiltration and fibre type switch. Early fibrosis was also apparent in the cardiac muscle. These histological modifications led to severe muscle, respiratory and cardiac functional impairments leading to premature death around 1 year. Moreover, DMD muscle exhibited systemic inflammation with a mixed M1/M2 phenotype. A comparative single cell RNAseq analysis of the diaphragm muscle was performed, revealing cellular populations alteration and molecular modifications in all muscle cell types. We show that DMD fibroadipogenic progenitors produced elevated levels of cartilage oligomeric matrix protein, a glycoprotein responsible for modulating homeostasis of extracellular matrix, and whose increased concentration correlated with muscle fibrosis both in R-DMDdel52 rats and human patients. Fibrosis is a component of tissue remodelling impacting the whole musculature of DMD patients, at the tissue level but most importantly at the functional level. We therefore propose that this specific biomarker can optimize the prognostic monitoring of functional improvement of patients included in clinical trials.</jats:p

    NR1D1 controls skeletal muscle calcium homeostasis through myoregulin repression

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    International audienceThe sarcoplasmic reticulum (SR) plays an important role in calcium homeostasis. SR calcium mishandling is described in pathological conditions, such as myopathies. Here, we investigated whether the nuclear receptor subfamily 1 group D member (NR1D1, also called REV-ERBα) regulates skeletal muscle SR calcium homeostasis. Our data demonstrate that NR1D1 deficiency in mice impaired sarco/endoplasmic reticulum calcium ATPase-dependent (SERCA-dependent) SR calcium uptake. NR1D1 acts on calcium homeostasis by repressing the SERCA inhibitor myoregulin through direct binding to its promoter. Restoration of myoregulin counteracted the effects of NR1D1 overexpression on SR calcium content. Interestingly, myoblasts from patients with Duchenne muscular dystrophy displayed lower NR1D1 expression, whereas pharmacological NR1D1 activation ameliorated SR calcium homeostasis and improved muscle structure and function in dystrophic mdx/Utr+/- mice. Our findings demonstrate that NR1D1 regulates muscle SR calcium homeostasis, pointing to its therapeutic potential for mitigating myopathy

    Operationalising emission and toxicity modelling of pesticides in LCA: the OLCA-Pest project contribution

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    Purpose Current field emission modelling and toxicity characterisation of pesticides suffer from several shortcomings like mismatches between LCI databases and LCIA methods, missing characterisation factors, missing environmental compartments, and environmental impact pathways. The OLCA-Pest project was implemented to address these aspects and to operationalise the assessment of pesticides in LCA. Based on this effort, we propose an approach to integrate pesticide emissions into LCI databases. Methods The PestLCI Consensus Model has been developed in order to estimate emission fractions to different environmental compartments. The initial distribution fractions should be linked to the compartments air, agricultural soil, natural soil, and freshwater. Emissions to off-field surfaces are hereby distributed between agricultural soil, natural soil, and freshwater by using surface cover data. Deposition on the crop surface should be recorded in an emission compartment crop with 13 sub-compartments for crop archetypes for both food and non-food uses. Default emission fractions are provided to calculate the emission fractions for different pesticide application scenarios. Results and discussion A sensitivity analysis shows the effects of the application technique, drift reduction, crop and development stage, field width, and buffer zone on the initial distribution fractions of field-applied pesticides. Recommendations are given for the implementation of a set of default initial distribution fractions into LCI databases, for the organisation of metadata, and for the modelling of pesticide residues in food along the supply chain (processing, storage). Priorities for further research are: improving the modelling of pesticide secondary emissions, further extending emission modeling (e.g. additional application techniques, including cover crops), considering metal-based pesticides in emission models, and systematically assessing human health impacts associated with pesticide residues in food crops. Conclusions The proposed approach allows to preserve the mass balance of the pesticide emitted after application, to make a consistent assessment of ecotoxicity and human toxicity, to define a clear and consistent interface between the LCI and LCIA phases, to estimate initial emission distribution fractions based on existing data, to document metadata transparently and efficiently within crop datasets, and to model the removal of pesticide residues in food during processing.info:eu-repo/semantics/publishedVersio

    Operationalising emission and toxicity modelling of pesticides in LCA: the OLCA-Pest project contribution

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    International audiencePurpose Current field emission modelling and toxicity characterisation of pesticides suffer from several shortcomings like mismatches between LCI databases and LCIA methods, missing characterisation factors, missing environmental compartments, and environmental impact pathways. The OLCA-Pest project was implemented to address these aspects and to operationalise the assessment of pesticides in LCA. Based on this effort, we propose an approach to integrate pesticide emissions into LCI databases. Methods The PestLCI Consensus Model has been developed in order to estimate emission fractions to different environmental compartments. The initial distribution fractions should be linked to the compartments air, agricultural soil, natural soil, and freshwater. Emissions to off-field surfaces are hereby distributed between agricultural soil, natural soil, and freshwater by using surface cover data. Deposition on the crop surface should be recorded in an emission compartment crop with 13 sub-compartments for crop archetypes for both food and non-food uses. Default emission fractions are provided to calculate the emission fractions for different pesticide application scenarios. Results and discussion A sensitivity analysis shows the effects of the application technique, drift reduction, crop and development stage, field width, and buffer zone on the initial distribution fractions of field-applied pesticides. Recommendations are given for the implementation of a set of default initial distribution fractions into LCI databases, for the organisation of metadata, and for the modelling of pesticide residues in food along the supply chain (processing, storage). Priorities for further research are: improving the modelling of pesticide secondary emissions, further extending emission modeling (e.g. additional application techniques, including cover crops), considering metal-based pesticides in emission models, and systematically assessing human health impacts associated with pesticide residues in food crops. Conclusions The proposed approach allows to preserve the mass balance of the pesticide emitted after application, to make a consistent assessment of ecotoxicity and human toxicity, to define a clear and consistent interface between the LCI and LCIA phases, to estimate initial emission distribution fractions based on existing data, to document metadata transparently and efficiently within crop datasets, and to model the removal of pesticide residues in food during processing

    Introducing ground cover management in pesticide emission modeling

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    Ground cover management (GCM) is an important agricultural practice used to reduce weed growth, erosion and runoff, and improve soil fertility. In the present study, an approach to account for GCM is proposed in the modeling of pesticide emissions to evaluate the environmental sustainability of agricultural practices. As a starting point, we include a cover crop compartment in the mass balance of calculating initial (within minutes after application) and secondary (including additional processes) pesticide emission fractions. The following parameters were considered: (i) cover crop occupation between the rows of main field crops, (ii) cover crop canopy density, and (iii) cover crop family. Two modalities of cover crop occupation and cover crop canopy density were tested for two crop growth stages, using scenarios without cover crops as control. From that, emission fractions and related ecotoxicity impacts were estimated for pesticides applied to tomato production in Martinique (French West Indies) and to grapevine cultivation in the Loire Valley (France). Our results demonstrate that, on average, the presence of a cover crop reduced the pesticide emission fraction reaching field soil by a factor of 3 compared with bare soil, independently of field crop and its growth stage, and cover crop occupation and density. When considering cover exported from the field, ecotoxicity impacts were reduced by approximately 65% and 90%, compared with bare soil for grapevine and tomato, respectively, regardless of the emission distribution used. Because additional processes may influence emission distributions under GCM, such as runoff, leaching, or preferential flow, further research is required to incorporate these processes consistently in our proposed GCM approach. Considering GCM in pesticide emission modeling highlights the potential of soil cover to reduce pesticide emissions to field soil and related freshwater ecotoxicity. Furthermore, the consideration of GCM as common farming practice allows the modeling of pesticide emissions in intercropping systems

    Pannexin-1 and Ca V 1.1 show reciprocal interaction during excitation-contraction and excitation-transcription coupling in skeletal muscle

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    International audienceOne of the most important functions of skeletal muscle is to respond to nerve stimuli by contracting. This function ensures body movement but also participates in other important physiological roles, like regulation of glucose homeostasis. Muscle activity is closely regulated to adapt to different demands and shows a plasticity that relies on both transcriptional activity and nerve stimuli. These two processes, both dependent on depolarization of the plasma membrane, have so far been regarded as separated and independent processes due to a lack of evidence of common protein partners or molecular mechanisms. In this study, we reveal intimate functional interactions between the process of excitation-induced contraction and the process of excitation-induced transcriptional activity in skeletal muscle. We show that the plasma membrane voltage-sensing protein CaV1.1 and the ATP-releasing channel Pannexin-1 (Panx1) regulate each other in a reciprocal manner, playing roles in both processes. Specifically, knockdown of CaV1.1 produces chronically elevated extracellular ATP concentrations at rest, consistent with disruption of the normal control of Panx1 activity. Conversely, knockdown of Panx1 affects not only activation of transcription but also CaV1.1 function on the control of muscle fiber contraction. Altogether, our results establish the presence of bidirectional functional regulations between the molecular machineries involved in the control of contraction and transcription induced by membrane depolarization of adult muscle fibers. Our results are important for an integrative understanding of skeletal muscle function and may impact our understanding of several neuromuscular diseases

    Clathrin plaques and associated actin anchor intermediate filaments in skeletal muscle

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    International audienceClathrin plaques are stable features of the plasma membrane observed in several cell types. They are abundant in muscle, where they localize at costameres that link the contractile apparatus to the sarcolemma and connect the sarcolemma to the basal lamina. Here, we show that clathrin plaques and surrounding branched actin filaments form microdomains that anchor a three-dimensional desmin intermediate filament (IF) web. Depletion of clathrin plaque and branched actin components causes accumulation of desmin tangles in the cytoplasm. We show that dynamin 2, whose mutations cause centronuclear myopathy (CNM), regulates both clathrin plaques and surrounding branched actin filaments, while CNM-causing mutations lead to desmin disorganization in a CNM mouse model and patient biopsies. Our results suggest a novel paradigm in cell biology, wherein clathrin plaques act as platforms capable of recruiting branched cortical actin, which in turn anchors IFs, both essential for striated muscle formation and function

    An embryonic CaVβ1 isoform promotes muscle mass maintenance via GDF5 signaling in adult mouse

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    International audienceDeciphering the mechanisms that govern skeletal muscle plasticity is essential to understand its pathophysiological processes, including age-related sarcopenia. The voltage-gated calcium channel CaV1.1 has a central role in excitation-contraction coupling (ECC), raising the possibility that it may also initiate the adaptive response to changes during muscle activity. Here, we revealed the existence of a gene transcription switch of the CaV1.1 subunit (CaV1) that is dependent on the innervation state of the muscle in mice. In a mouse model of sciatic denervation, we showed increased expression of an embryonic isoform of the subunit that we called CaV1E. CaV1E boosts downstream growth differentiation factor 5 (GDF5) signaling to counteract muscle loss after denervation in mice. We further reported that aged mouse muscle expressed lower quantity of CaV1E compared with young muscle, displaying an altered GDF5-dependent response to denervation. Conversely, CaV1E overexpression improved mass wasting in aging muscle in mice by increasing GDF5 expression. We also identified the human CaV1E analogous and show a correlation between CaV1E expression in human muscles and age-related muscle mass decline. These results suggest that strategies targeting CaV1E or GDF5 might be effective in reducing muscle mass loss in aging
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