Biology subjects

Musaro, A.

Publications and source records attributed to Musaro, A..

3 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↗

bioRxiv2022

The long noncoding RNA Charme supervises cardiomyocytes maturation by controlling cell differentiation programs in the developing heart

Long noncoding RNAs (lncRNAs) are emerging as critical regulators of heart physiology and disease, although the studies unveiling their modes-of-action are still limited to few examples. We recently identified pCharme, a chromatin-associated lncRNA whose functional knockout in mice results in defective myogenesis and morphological remodelling of the cardiac muscle. Here, we combined Cap-Analysis of Gene Expression (CAGE), single-cell (sc)RNA sequencing and whole-mount in situ hybridization analyses to study pCharme cardiac expression. Since the early steps of cardiomyogenesis, we found the lncRNA being specifically restricted to cardiomyocytes, where it assists the formation of specific nuclear condensates containing MATR3, as well as important RNAs for cardiac development. In line with the functional significance of these activities, pCharme ablation in mice results in a delayed maturation of cardiomyocytes, which ultimately leads to morphological alterations of the myocardium and ventricular hypo-trabeculation. Since congenital anomalies in myocardium are clinically relevant in humans and predispose patients to major complications, the identification of novel genes controlling cardiac morphology becomes crucial. Our study offers unique insights into a novel lncRNA-mediated regulatory mechanism promoting cardiomyocyte maturation and bears relevance to Charme locus for future theranostic applications.

molecular biology↗

bioRxiv2020

Engineered extracellular vesicle decoy receptor-mediated modulation of the IL6 trans-signalling pathway in muscle

The cytokine interleukin 6 (IL6) is a key mediator of inflammation that contributes to skeletal muscle pathophysiology. IL6 activates target cells by two different mechanisms, the classical and transsignalling pathways. While classical signalling is associated with the anti-inflammatory activities of the cytokine, the IL6 trans-signalling pathway mediates chronic inflammation and is therefore a target for therapeutic intervention. Extracellular vesicles (EVs) are natural, lipid-bound nanoparticles, with potential as targeted delivery vehicles for therapeutic macromolecules. Here, we engineered EVs to express IL6 signal transducer (IL6ST) decoy receptors to selectively inhibit the IL6 trans-signalling pathway. The potency of the IL6ST decoy receptor EVs was optimized by inclusion of a GCN4 dimerization domain and a peptide sequence derived from syntenin-1 which targets the decoy receptor to EVs. The resulting engineered EVs were able to efficiently inhibit activation of the IL6 transsignalling pathway in reporter cells, while having no effect on the IL6 classical signalling. IL6ST decoy receptor EVs, were also capable of blocking the IL6 trans-signalling pathway in C2C12 myoblasts and myotubes, thereby inhibiting the phosphorylation of STAT3 and partially reversing the anti-differentiation effects observed when treating cells with IL6/IL6R complexes. Treatment of a Duchenne muscular dystrophy mouse model with IL6ST decoy receptor EVs resulted in a reduction in STAT3 phosphorylation in the quadriceps and gastrocnemius muscles of these mice, thereby demonstrating in vivo activity of the decoy receptor EVs as a potential therapy. Taken together, this study reveals the IL6 trans-signalling pathway as a promising therapeutic target in DMD, and demonstrates the therapeutic potential of IL6ST decoy receptor EVs.

molecular biology↗