GDF5

La sarcopénie est une maladie musculaire complexe liée à l’âge qui affecte entre 10 à 16 % des personnes âgées de plus 65 ans. Elle se caractérise par une perte excessive de la masse musculaire et de la force. Malgré la multitude d’études visant à comprendre les mécanismes physiologiques qui sous-tendent cette pathologie, la physiopathologie de la sarcopénie reste encore mal comprise. A ce jour, il n’existe pas de traitement pharmacologique pour lutter contre cette pathologie. Dans ce contexte, notre équipe développe des approches thérapeutiques basées sur l’utilisation de la protéine GDF5 pour contrecarrer la perte de la masse et de la fonction musculaire dans diverses conditions pathologiques dont la sarcopénie. Après avoir décrypté un des mécanismes moléculaires régulant l’expression du GDF5, nous avons démontré le potentiel thérapeutique de cette protéine dans la préservation de la masse et la force musculaire chez les souris âgées

New insights in CaVβ subunits: role in the regulation of gene expression and cellular homeostasis

International audienceThe voltage-gated calcium channels (CaVs or VGCCs) are fundamental regulators of intracellular calcium homeostasis. When electrical activity induces their activation, the influx of calcium that they mediate or their interaction with intracellular players leads to changes in intracellular Ca2+ levels which regulate many processes such as contraction, secretion and gene expression, depending on the cell type. The essential component of the pore channel is the CaVα1 subunit. However, the fine-tuning of Ca2+-dependent signals is guaranteed by the modulatory role of the auxiliary subunits β, α2δ, and γ of the CaVs. In particular, four different CaVβ proteins (CaVβ1, CaVβ2, CaVβ3, and CaVβ4) are encoded by four different genes in mammalians, each of them displaying several splice variants. Some of these isoforms have been described in regulating CaVα1 docking and stability at the membrane and controlling the channel complex's conformational changes. In addition, emerging evidences have highlighted other properties of the CaVβ subunits, independently of α1 and non-correlated to its channel or voltage sensing functions. This review summarizes the recent findings reporting novel roles of the auxiliary CaVβ subunits and in particular their direct or indirect implication in regulating gene expression in different cellular contexts

rGdf5, an unexpected treatment against age-related muscle mass loss

Voir document du dépôt hal-04001930.International audienc

Neural circuit repair by low-intensity magnetic stimulation requires cellular magnetoreceptors and specific stimulation patterns

International audienceAlthough electromagnetic brain stimulation is a promising treatment in neurology and psychiatry, clinical outcomes are variable, and underlying mechanisms are ill-defined, which impedes the development of new effective stimulation protocols. Here, we show, in vivo and ex vivo, that repetitive transcranial magnetic stimulation at low-intensity (LI-rTMS) induces axon outgrowth and synaptogenesis to repair a neural circuit. This repair depends on stimulation pattern, with complex biomimetic patterns being particularly effective, and the presence of cryptochrome, a putative magnetoreceptor. Only repair-promoting LI-rTMS patterns up-regulated genes involved in neuronal repair; almost 40% of were cryptochrome targets. Our data open a new framework to understand the mechanisms underlying structural neuroplasticity induced by electromagnetic stimulation. Rather than neuronal activation by induced electric currents, we propose that weak magnetic fields act through cryptochrome to activate cellular signaling cascades. This information opens new routes to optimize electromagnetic stimulation and develop effective treatments for different neurological diseases

Exploring the protective role of GDF5 against skeletal muscle disuse atrophy

International audienceSkeletal muscle is a high plastic tissue able to change its mass upon different stimuli accordingly with environmental changes. Its adaptability depends on many factors and is based on complex mechanisms. Among the process that could alter muscle mass homeostasis, disuse and inactivity induce strong muscle mass and function decrease, having heavy impact on life quality and requiring long time to recover. Growth Differentiation Factor 5 (GDF5) is a crucial player in muscle homeostasis, shown to counteract both denervation- and age-related muscle wasting by limiting the activation of catabolic signals. However, its effects on disuse atrophy following muscle immobilization has to be investigated. In order to establish a potential therapeutic tool having a wide relevance, ranging from disease to microgravity exposure (space flight), we evaluated the consequences of GDF5 overexpression after 10 days of immobilization and 3 weeks of release of hind limb mouse muscles. We observed that local GDF5 overexpression in posterior limbs improved muscle mass loss during immobilization. However, three weeks after release, muscle mass and function were not affected by GDF5 overexpression. We aim to better characterize the effect of GDF5 treatment on several morphological and functional parameters of skeletal muscle upon immobilization/release. In addition, we will assess its eventual benefits at shorter time points after release, in order to establish if GDF5-based treatment could be proposed to shorten the time-window needed for optimal muscle recovery after disuse.In parallel, a study of microgravity exposure was carried on a muscle cell line. We showed that, in the absence of gravity, myotube formation was inhibited, suggesting that this condition could impact cytoskeleton and fusion capability. We will establish if GDF5 treatment might be beneficial for myoblast fusion and myotube morphology during microgravity exposure. In conclusion, our preliminary results suggest that a treatment based on GDF5 could have a therapeutic potential to ameliorate the pathophysiology of muscle during disuse condition to be applied also to space flight and microgravity exposure