Biomimetic patterns of weak magnetic pulses modify gene expression and need cryptochrome to induce cerebellar reinnervation.

CaVβ1E boosts downstream growth differentiation factor 5 signaling to counteract muscle mass loss in denervated or aged mouse muscles.

Voltage-gated Ca²⁺ channels (VGCCs) are regulated by four CaVβ subunits (CaVβ1–CaVβ4), each showing specific expression patterns in excitable cells. While primarily known for regulating VGCC function, CaVβ proteins also have channel-independent roles, including gene expression modulation. Among these, CaVβ1 is expressed in skeletal muscle as multiple isoforms. The adult isoform, CaVβ1D, localizes at the triad and modulates CaV1 activity during Excitation–Contraction Coupling (ECC). In this study, we investigated the lesser-known embryonic/perinatal CaVβ1 isoforms and their roles in neuromuscular junction (NMJ) formation, maturation, and maintenance. We found that CaVβ1 isoform expression is developmentally regulated through differential promoter activation. Specifically, CaVβ1A is expressed in embryonic muscle and reactivated in denervated adult muscle, alongside the known CaVβ1E isoform. Nerve injury in adult muscle triggers a shift in promoter usage, resulting in re-expression of embryonic/perinatal Cacnb1A and Cacnb1E transcripts. Functional analyses using aneural agrin-induced AChR clustering on primary myotubes demonstrated that these isoforms contribute to NMJ formation. Additionally, their expression during early post-natal development is essential for NMJ maturation and long-term maintenance. These findings reveal previously unrecognized roles of CaVβ1 isoforms beyond VGCC regulation, highlighting their significance in neuromuscular system development and homeostasis.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-22104-4

Amyotrophic lateral sclerosis is characterized by the progressive dismantling of the motor unit. While “dying back” hypothesis suggests that peripheral neuromuscular dysfunction precedes motor neuron loss, the molecular mechanisms limiting endogenous compensatory responses remain poorly understood. We longitudinally examined neuromuscular decline and GDF5-SMAD1/5/8 signaling in SOD1 ^G93A mice. Our findings revealed a translational checkpoint linked to the lncRNA Myoparr that suppresses GDF5 production at symptom onset. To overcome this deficit, we delivered AAV9-GDF5 at the symptomatic stage. GDF5 supplementation restored SMAD signaling balance, shifting the motor unit from a pro-atrophic TGF-β-SMAD2/3 toward a pro-myogenic SMAD1/5 profile. Treatment preserved muscle mass, reduced mitochondrial reactive oxygen species, and maintained neuromuscular junction integrity, including peri-synaptic glial support. GDF5 also promoted molecular recovery of spinal MNs by enhancing homeostatic marker expression. Together, these findings identify GDF5 as a multimodal stabilizer of the motor unit and highlight its potential as therapeutic target in combinatorial strategies aimed at coupling motor unit stabilization with central neuroprotective interventions.

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. Sarcopenia is a complex age-related muscular disease affecting 10 to 16 % of people over 65 years old. It is characterized by excessive loss of muscle mass and strength. Despite a plethora of studies aimed at understanding the physiological mechanisms underlying this pathology, the pathophysiology of sarcopenia remains poorly understood. To date, there is no pharmacological treatment for this disease. In this context, our team develop therapeutic approaches based on the GDF5 protein to counteract the loss of muscle mass and function in various pathological conditions, including sarcopenia. After deciphering one of the molecular mechanisms governing GDF5 expression, we have demonstrated the therapeutic potential of this protein in the preservation of muscle mass and strength in aged mice.