Stimulating endogenous repair in congenital muscular dystrophy

Les dystrophies musculaires sont des maladies génétiques sévères, dégénératives et incurables. Ces maladies sont caractérisées par une perte de masse musculaire, une diminution de l’espérance de vie ainsi qu’une mobilité limitée. Des mutations dans les protéines responsables de l’attache des fibres musculaires à la matrice extracellulaire rendent les fibres plus fragiles et susceptibles à la rupture lors de la contraction musculaire. Des cycles continus de dégénération et régénération mènent à une inflammation chronique, à l’épuisement des cellules souches, à l’accumulation de tissu fibreux et limitent la fonction du muscle. Puisqu’aucun traitement ne s’est révélé efficace lors d’essais cliniques, l’absence de solutions à ce jour pour alléger les symptômes des patients rend la recherche d’approches alternatives essentielle. Nous proposons ici que la stimulation de la régénération est une nouvelle approche qui permet de restaurer et maintenir la fonction du muscle. Cette étude porte sur l’utilisation de l’Apéline-13, un candidat prometteur pour le traitement de la dystrophie musculaire. L’Apéline-13 est un peptide endogène longtemps étudié pour son rôle dans le contrôle du métabolisme et comme régulateur du système cardiovasculaire chez la souris. Récemment, il a été révélé que l’Apéline-13 stimule la fonction des cellules souches musculaires. Nos résultats montrent que le traitement systémique à l’Apéline-13 mobilise les cellules souches musculaires, augmentant grandement la régénération du muscle squelettique, et améliorant drastiquement les performances motrices dans le modèle de Dystrophie Musculaire Congénitale DyW/DyW. De plus, aucun effet secondaire n’a été observé et le traitement a été bien toléré par les souris. Il s’agit de résultats importants, considérant l’absence de traitements efficaces pour la gestion des dystrophies musculaires. L’industrie pharmaceutique connait aussi un intérêt récent pour la recherche dans le domaine des maladies rares. Un composé avec un effet bénéfique sur l’état de santé dans la dystrophie musculaire pourrait avoir un effet drastique sur la vie des patients.Abstract : Muscular dystrophies are severe, degenerative diseases for which no efficient therapeutic options exist. These diseases are characterized by muscle wasting, limited life expectancy and reduced ambulatory capacities. Mutations in proteins implicated in the attachment of muscle fibers to the extracellular matrix cause the fibers to be more fragile, making them more susceptible to rupture under physical stress. Asynchronous multifocal cycles of degeneration and regeneration of the muscle leads to chronic inflammation, stem cell exhaustion, and fibrotic tissue accumulation ultimately impairing muscle function severely. Up to this day, experimental treatments have all met various pitfalls and none have reached the clinics. Thus, research into novel viable approaches to alleviate diseases symptoms is much needed. Here, we propose a novel treatment approach for muscular dystrophy, that is centered on stimulating muscle stem cell (MuSC) function which leads to an increase in the endogenous regenerative capacity allowing to maintain muscle function. We describe the use of Apelin-13 as a potential candidate for the treatment of muscular dystrophy. Apelin is an endogenous peptide that has been studied for many years in relation to its beneficial effect on the cardiovascular system and its anti-diabetic effects in mice. More recently, Apelin has also been shown to be a MuSC stimulatory factor. We show here that systemic Apelin-13 administration stimulates MuSC numbers and boosts skeletal muscle regeneration and thereby increases motor function in the DyW/DyW model of Congenital Muscular Dystrophy. No adverse effects were observed, and Apelin-13 treatment was well tolerated in mice. This discovery is of major importance considering the absence of alternative efficient treatments for these severe degenerative diseases. There is great translational potential associated with this research as many compagnies have grown interest in rare disease research over the last decade. A drug with a beneficial impact on disease state in muscular dystrophy could have drastic effects on the life of patients

Synthesis and Characterization in Vitro and in Vivo of (l)‑(Trimethylsilyl)alanine Containing Neurotensin Analogues

The silylated amino acid (l)-(trimethylsilyl)­alanine (TMSAla) was incorporated at the C-terminal end of the minimal biologically active neurotensin (NT) fragment, leading to the synthesis of new hexapeptide NT[8–13] analogues. Here, we assessed the ability of these new silylated NT compounds to bind to NTS1 and NTS2 receptors, promote regulation of multiple signaling pathways, induce inhibition of the ileal smooth muscle contractions, and affect distinct physiological variables, including blood pressure and pain sensation. Among the C-terminal modified analogues, compound <b>6</b> (JMV2007) carrying a TMSAla residue in position 13 exhibits a higher affinity toward NT receptors than the NT native peptide. We also found that compound <b>6</b> is effective in reversing carbachol-induced contraction in the isolated strip preparation assay and at inducing a drop in blood pressure. Finally, compound <b>6</b> produces potent analgesia in experimental models of acute and persistent pain

In vivo transcriptomic profiling using cell encapsulation identifies effector pathways of systemic aging

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.We thank Phoukham Phothirath and Oliver Rizzo of the preclinical investigations group of Nestlé Research for expert advice and support with in vivo experiments. OM, JNF, and CFB are supported by the Fondation Suisse de Recherche sur les Maladies Musculaires (FSRMM). CFB is supported by the Canadian Institutes of Health Research (CIHR, PJT-162442), the Natural Sciences and Engineering Research Council of Canada (NSERC, RGPIN-2017-05490), the Fonds de Recherche du Québec – Santé (FRQS, Dossiers 296357, 34813, and 36789), the ThéCell Network (supported by the FRQS), the Canadian Stem Cell Network, and a research chair of the Centre de Recherche Médicale de l’Université de Sherbrooke (CRMUS). PMC is supported by ERC-2016-AdG-741966, La Caixa-HEALTH-HR17-00040, MDA, AFM, MWRF, UPGRADE-H2020-825825, RTI2018-096068-B-I00, a María de Maeztu Unit of Excellence award to UPF (MDM-2014-0370), and a Severo Ochoa Center of Excellence award to the CNIC (SEV-2015-0505). XH is recipient of a Severo Ochoa FPI (SEV-2015-0505-17-1) predoctoral fellowship