Biology subjects

Le Moal, E.

Publications and source records attributed to Le Moal, E..

5 recordsLinked to original sources

bioRxiv2026

Restoration of Capacity to Build Muscle Strength in Geriatric Mice by Inhibition of the Gerozyme 15-Prostaglandin Dehydrogenase

Loss of skeletal muscle mass and strength with age drives sarcopenia, a syndrome affecting >100 million people worldwide that leads to loss of mobility, independence, and increased mortality. Mechanical overload induces hypertrophy in young muscle, but this response is markedly attenuated with age--a poorly understood phenomenon termed "anabolic resistance." Here we test whether impaired paracrine communication between myofibers and their niche underlies this loss of plasticity in geriatric mice. In aged muscle, pharmacological inhibition of 15-PGDH restores prostaglandin E2 (PGE2) bioavailability and rescues the anabolic response, increasing muscle growth and contractile strength. Single-nuclei RNA-seq revealed a paracrine circuit: PGE2 drives IGF1 synthesis in type IIb myonuclei, which signals to stromal, myogenic, myonuclear, and immune cells. Blocking IGF1 receptor signaling abolished these gains, placing PGE2 upstream of an IGF1-mediated circuit that coordinates multicellular hypertrophy. Thus, 15-PGDH inhibition is a pharmacological strategy to overcome the anabolic resistance and rebuild muscle in aging.

cell biology↗

bioRxiv2026

15-PGDH Inhibition Overcomes Muscle Regenerative Deficit Seen With GLP1-Receptor Agonist-Induced Weight Loss

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), including long-acting semaglutide, are revolutionary anti-obesity therapies. However, emerging evidence indicates that weight loss may come at the expense of skeletal muscle mass, a tissue essential for mobility, metabolic regulation, and overall health. Here, we show that an inhibitor of the gerozyme 15-hydroxyprostaglandin dehydrogenase (PGDHi), which boosts PGE2 levels, increases skeletal muscle mass, strength, and regeneration in the presence of semaglutide. We find that in a high fat diet-induced mouse model of obesity, semaglutide alone induces significant loss of muscle mass, while retaining contractile function. However, muscle regeneration and recovery of strength post-injury are hindered by semaglutide. This regenerative deficit is due to impeded stem cell function, which is overcome if mice are treated with a combination of PGDHi and semaglutide. Our data show that GLP-1-mediated weight loss interferes with this key muscle-building function, which PGDHi co-treatment counteracts to promote proper muscle regeneration and restored strength.

cell biology↗

bioRxiv2024

Macrophage-derived RNAseT2 stimulates muscle stem cell fusion via SLK/N-WASP/actin bundling

Muscle stem cells (MuSCs) fuse to form myofibers to repair skeletal muscle after injury. Within the regenerative MuSC niche, restorative macrophages stimulate MuSC fusion, although the molecular mechanisms involved are largely unknown. Here, we show that restorative macrophages secrete ribonuclease T2 (RNAseT2) to stimulate MuSC fusion. RNAseT2 entered MuSCs via the mannose receptor and induced the formation of actin bundles in MuSCs, enabling cell/cell fusion. Mechanistically, RNAseT2 bound to Ste20-like kinase (SLK), which itself triggered the phosphorylation-mediated activation of N-WASP, through Paxillin phosphorylation, allowing actin bundling necessary for MuSC fusion. In vivo, overexpressing RNAseT2 in regenerating muscle increased fusion in newly formed myofibers in mouse and zebrafish while macrophages deficient for RNAseT2 gene led to fusion defect and smaller myofibers. This study reveals a new function for the highly conserved RNAseT2 and provides a new molecular mechanism by which restorative macrophages support MuSC fusion during muscle repair.

cell biology↗

bioRxiv2022

Apelin Stimulation of the Perivascular MuSC Niche Enhances Endogenous Repair in Muscular Dystrophy

Impaired skeletal muscle stem cell (MuSC) function has long been suspected to contribute to the pathogenesis of muscular dystrophy (MD). Here we describe that defects in the endothelial cell (EC) compartment of the perivascular stem cell niche in three different types of MD are associated with inefficient mobilization of MuSCs following tissue damage. Using chemoinformatic analysis, we identified the 13 amino acid form of the peptidic hormone apelin (AP-13) as a candidate for systemic stimulation of skeletal muscle ECs. In dystrophic mice, administration of AP-13 generates a pro-myogenic EC-rich niche that supports MuSC function and markedly improves tissue regeneration, muscle strength, and physical performance. Moreover, we demonstrate that EC specific knockout of the AP-13 receptor leads to regenerative defects that phenocopy major pathological features of MD. Altogether, we provide in vivo proof-of-concept that enhancing endogenous repair by targeting the perivascular niche is a viable therapeutic avenue for MD and characterize AP-13 as a novel drug candidate for systemic treatment of stem cell dysfunction.

cell biology↗

bioRxiv2020

In-vivo Transcriptomic Profiling of Systemic Aging using Cell Encapsulation

Sustained exposure to a young systemic environment rejuvenates aged organisms and promotes cellular function. However, due to the intrinsic complexity of tissues it remains challenging to pinpoint niche-independent effects of circulating factors on specific cell populations. Here we describe a method for the encapsulation of human and mouse skeletal muscle progenitors in diffusible polyethersulfone hollow fiber capsules that can be used to profile systemic aging in vivo independent of heterogeneous short-range tissue interactions. We observed that circulating long-range signaling factors in the old systemic environment lead to an activation of Myc and E2F transcription factors, induce senescence and suppress myogenic differentiation. Importantly, in vitro profiling using young and old serum in 2D culture does not capture all pathways deregulated in encapsulated cells in aged mice. Thus, in vivo transcriptomic profiling using cell encapsulation allows for the characterization of effector pathways of systemic aging with unparalleled accuracy.

bioengineering↗