Biology subjects

Messeant, J.

Publications and source records attributed to Messeant, J..

5 recordsLinked to original sources

bioRxiv2026

GDF5 as a Multimodal Protector of the Motor Unit in Amyotrophic Lateral Sclerosis

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 SOD1G93A 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-{beta}-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.

physiology↗

bioRxiv2024

Targeted-SMN insufficiency in Skeletal Muscle Stem Cells mediates non-cell autonomous loss of motor neurons at long term

Spinal Muscular Atrophy (SMA) is due to a deficit in SMN protein encoded by the SMN1 gene. SMN-targeted disease modifying treatments have greatly improved the clinical outcomes of this neuromuscular disease. However, uncertainties remain regarding their long-term efficacy and non-neuronal tissue involvement in disease progression. We found that SMA type II patient muscles display a reduced number of quiescent PAX7+ Muscle Stem Cells (MuSC). In SMA mice, we showed that SMN is an important regulator of myogenic progenitor fate during early postnatal growth. In Pax7 Cre-driven conditional knockout mouse models, we demonstrated that high levels of SMN are required to ensure the maintenance of the quiescent MuSC pool in adult muscle. We further established that depletion of SMN-deficient MuSC yielded neuromuscular junctions remodeling followed by a non-cell autonomous loss of motor neurons in the long term. Overall, our findings demonstrate that MuSC are a crucial therapeutic target for SMA treatment. HIGHLIGHTSO_LISMN regulates myogenic lineage progression and quiescent MuSC pool establishment during postnatal growth C_LIO_LIBoth Smn alleles are necessary for the survival of quiescent MuSC in adult muscle C_LIO_LIDepletion of SMN-deficient MuSC leads to NMJ remodeling and non-cell autonomous loss of MN C_LI

pathology↗

bioRxiv2020

Muscle Van Gogh-like 2 shapes the neuromuscular synapse by regulating MuSK signaling activity

The development of the neuromuscular junction (NMJ) requires dynamic trans-synaptic coordination orchestrated by secreted factors, including the morphogens of the Wnt family. Yet, how the signal of these synaptic cues is transduced, and particularly during the regulation of acetylcholine receptor (AChR) accumulation in the postsynaptic membrane remains unclear. We explored the function of Van Gogh-Like protein 2 (Vangl2), a core component of Wnt planar cell polarity signaling. We showed that the conditional genetic ablation of Vangl2 in muscle reproduces the NMJ differentiation defects in mice with constitutive Vangl2 deletion. These alterations persisted into adulthood with NMJs disassembly leading to an impairment of neurotransmission and motor function deficits. Mechanistically, we found that Vangl2 and the muscle-specific kinase MuSK acted in the same genetic pathway and that Vangl2 binds MuSK, thus controlling its signaling activity. Our results identify Vangl2 as a key player of the core complex of molecules shaping neuromuscular synapses and shed light on the molecular mechanisms underlying NMJ assembly.

neuroscience↗

bioRxiv2020

Lamin-related congenital muscular dystrophy alters mechanical signaling and skeletal muscle growth

BackgroundLaminopathies are a clinically heterogeneous group of disorders caused by mutations in the LMNA gene, which encodes the nuclear envelope proteins lamins A and C. The most frequent diseases associated with LMNA mutations are characterized by skeletal and cardiac involvement, and include autosomal dominant Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy type 1B, and LMNA-related congenital muscular dystrophy (LMNA-CMD). Although the exact pathophysiological mechanisms responsible for LMNA-CMD are not yet understood, severe contracture and muscle atrophy suggest that impair skeletal muscle growth may contribute to the disease severity. MethodsWe used human muscle stem cells (MuSCs) carrying 4 different LMNA mutations and two mouse models of muscle laminopathies, representing a spectrum of disease severity, to investigate the ability of skeletal muscle to differentiate and to hypertrophy in response to mechanical challenges. We extended these finding to individuals with LMNA-related muscular dystrophy using muscle biopsies. ResultsIn vitro, we observe impaired myogenic differentiation with disorganized cadherin/{beta} catenin adhesion complexes in MuSCs carrying LMNA-CMD. We show that skeletal muscle from Lmna-CMD mice is unable to hypertrophy in response to functional overload, due to defective accretion of activated MuSCs, defective protein synthesis and defective remodeling of the neuro-muscular junction. Moreover, stretched myotubes and overloaded muscle fibers with LMNA-CMD mutations display aberrant mechanical regulation of the Yes-Associated Protein (YAP), a key sensor and mediator of mechanical cues. We also observe defects in MuSC activation and YAP signaling in muscle biopsies from LMNA-CMD patients. These phenotypes are not recapitulated in closely-related EDMD models. ConclusionsCombining studies in vitro, in vivo and patient samples, we find that LMNA-CMD mutations interfere with mechano-signaling pathways in skeletal muscle, implicating defective skeletal muscle growth as a pathogenic contributor for the severity of LMNA-related muscular dystrophy.

physiology↗

bioRxiv2019

Desmin is a modifier of dystrophic muscle features in Mdx mice

Duchenne muscular dystrophy (DMD) is a severe neuromuscular disease, caused by dystrophin deficiency. Desmin is like dystrophin associated to costameric structures bridging sarcomeres to extracellular matrix that are involved in force transmission and skeletal muscle integrity. In the present study, we wanted to gain further insight into the roles of desmin which expression is increased in the muscle from the mouse Mdx DMD model. We show that a deletion of the desmin gene (Des) in Mdx mice (DKO, Mdx:desmin-/-) induces a marked worsening of the weakness (reduced maximal force production) as compared to Mdx mice. Fragility (higher susceptibility to contraction-induced injury) was also aggravated and fatigue resistance was reduced in DKO mice. Moreover, in contrast to Mdx mice, the DKO mice did not undergo a muscle hypertrophy because of smaller and less numerous fibers, with reduced percentage of centronucleated fibres. Interestingly, Desmin cDNA transfer with adeno-associated virus in 1-month-old DKO mice and newborn Mdx mice improved muscle weakness. Overall, desmin plays important and beneficial roles on muscle performance, fragility and remodelling in dystrophic Mdx mice.

pathology↗