Biology subjects

Gineste, C.

Publications and source records attributed to Gineste, C..

4 recordsLinked to original sources

bioRxiv2025

Elucidating the molecular landscape of centronuclear myopathies in mouse models: an integrative multi-omics and network analysis

Centronuclear myopathies (CNM) are rare inherited muscle disorders characterized by muscle atrophy, weakness, and altered muscle fiber structure, primarily due to mutations in genes like MTM1, DNM2, and BIN1. The pathomechanisms implicated in CNM are only partially understood, and no curative therapies are available for patients. This study exploits a unique multi-omics dataset and network-based analyses to elucidate the molecular pathways involved in CNM. First, we performed Weighted Gene Co-expression Network Analysis (WGCNA) to identify gene modules correlated with CNM phenotypes. We find that modules correlated to a positive muscular phenotype were enriched for genes involved in muscle contraction, RNA processes and oxidative phosphorylation, while modules associated with impaired muscle structure and function were enriched in immune response, innervation, vascularization processes, and fatty acid oxidation. Next, we integrated transcriptomic, proteomic, and metabolomic data from the Mtm1-/y mouse model with public knowledge bases using a multilayer network approach and explored the network using a random walk with restart approach. This study revealed novel metabolites that could be targeted through dietary supplementation as potential therapeutic strategies. Our findings demonstrate how multi-omics network analyses can reveal new aspects of CNM pathomechanisms and identify avenues for intervention.

bioinformatics↗

bioRxiv2022

Cyclosporin A delays the terminal disease stage in Tfam KO mice without improving mitochondrial energy production

AO_SCPLOWBSTRACTC_SCPLOWMitochondrial myopathies are rare genetic disorders characterized by muscle weakness and exercise intolerance. Currently, no effective treatment exists for these myopathies. Interestingly, the pharmacological cyclophilin inhibitor cyclosporine A (CsA) extended lifespan and prevented loss of force and mitochondrial Ca2+ overload in muscle fibers in the skeletal muscle-specific Tfam knockout mouse model of lethal mitochondrial myopathy (Tfam KO). The unaffected expression of proteins involved in mitochondrial energy metabolism suggests that these improvements occurred without improvement in metabolism. In this study, we aimed at investigating the effects of four weeks of CsA administration on in vivo contractile function and mitochondrial energy production in Tfam KO mice. The treatment started before the terminal phase with severe muscle weakness and weight loss. Our results show that CsA treatment delayed progression into the terminal disease phase. This occurred without any obvious positive effects on mitochondrial energy production at rest or during fatigue induced by repeated contractions. In conclusion, cyclophilin inhibitors may have the potential of counteracting devastating muscle weakness in patients with mitochondrial myopathies most probably by preventing deleterious effects triggered by excessive mitochondrial Ca2+ uptake rather than by improving mitochondrial energy production.

pathology↗

bioRxiv2021

Cytoskeleton-extracellular matrix interaction is required to maintain mitochondrial Ca2+ control in mouse skeletal muscle fibre

Cells rapidly lose their physiological phenotype upon disruption of their extracellular matrix (ECM)-intracellular cytoskeleton interactions. Here, we investigated acute effects of ECM disruption on cellular and mitochondrial morphology, transcriptomic signatures, and Ca2+ handling in adult mouse skeletal muscle fibers. Adult skeletal muscle fibers were isolated from mouse toe muscle either by collagenase-induced dissociation of the ECM or by mechanical dissection that leaves the contiguous ECM intact. Experiments were generally performed four hours after cell isolation. At this time, there were striking differences in the gene expression patterns between fibers isolated with the two methods; 24h after cell isolation, enzymatically dissociated fibers had transcriptomic signatures resembling dystrophic phenotypes. Mitochondrial appearance was grossly similar in the two groups, but 3D electron microscopy revealed shorter and less branched mitochondria in enzymatically dissociated than in mechanically dissected fibers. Similar increases in free cytosolic [Ca2+] during repeated tetanic stimulation were accompanied by marked mitochondrial Ca2+ uptake only in enzymatically dissociated muscle fibers. The aberrant mitochondrial Ca2+ uptake was partially prevented by the mitochondrial Ca2+ uniporter inhibitor Ru360 and by cyclosporine A and NV556, which inhibit the mitochondrial protein Ppif (also called cyclophilin D). Importantly, inhibition of Ppif with NV556 significantly improved survival of mice with mitochondrial myopathy in which muscle mitochondria take up excessive amounts of Ca2+ even with an intact ECM. In conclusion, skeletal muscle fibers isolated by collagenase-induced dissociation of the ECM display aberrant mitochondrial Ca2+ uptake, which involves a Ppif-dependent mitochondrial Ca2+ influx resembling that observed in mitochondrial myopathies.

physiology↗

bioRxiv2017

L-tyrosine supplementation is not therapeutic for skeletal muscle dysfunction in zebrafish and mouse models of dominant skeletal muscle α-actin nemaline myopathy.

Nemaline myopathy (NM) is a skeletal muscle disorder with no curative treatment. Although L-tyrosine administration has been indicated to provide benefit to patients, previous studies have been limited due to sample size or not testing for raised L-tyrosine levels. We evaluated the efficacy of L-tyrosine treatment to improve skeletal muscle function in three animal models of NM caused by skeletal muscle -actin (ACTA1) mutations. Firstly we determined the maximum safest L-tyrosine concentration for inclusion in the water of wildtype zebrafish. We then treated NM TgACTA1D286G-eGFP zebrafish from 24 hours post fertilization with the highest safe L-tyrosine dose (10 {micro}M). At 6 days post fertilization, no significant improvement was detected in skeletal muscle function (swimming distance). We also determined the highest safe L-tyrosine dose for dietary L-tyrosine supplementation to wildtype mice. Next we treated the NM TgACTA1D286G mouse model continuously from preconception with 2% L-tyrosine supplemented to regular feed. We examined skeletal muscles at 6-7 weeks using indicators of skeletal muscle integrity: bodyweight, voluntary running wheel and rotarod performance, all parameters previously shown to be reduced in TgACTA1D286G mice. The L-tyrosine treatment regime did not result in any improvement of these parameters, despite significant elevation of free L-tyrosine levels in sera (57%) and quadriceps muscle (45%) of treated TgACTA1D286G mice. Additionally, we assessed the effects of 4 weeks of 2% L-tyrosine dietary supplementation on skeletal muscle function of older (6-7 month old) NM TgACTA1D286G and KIActa1H40Y mice. This dosing regime did not improve decreased bodyweight, nor the mechanical properties, energy metabolism, or atrophy of skeletal muscles in these NM models. Together these findings demonstrate that with the treatment regimes and doses evaluated, L-tyrosine does not therapeutically modulate dysfunctional skeletal muscles in NM animal models with dominant ACTA1 mutations. Therefore this study yields important information on aspects of the clinical utility of L-tyrosine for ACTA1 NM.\n\nSummary statementDespite previous encouraging reports, this study utilising zebrafish and mouse models of nemaline myopathy shows no therapeutic benefit on skeletal muscle functionality in response to L-tyrosine supplementation.

neuroscience↗