Gpr18 agonist dampens inflammation, enhances myogenesis, and restores muscle function in models of Duchenne muscular dystrophy

Introduction: Muscle wasting in Duchenne Muscular Dystrophy is caused by myofiber fragility and poor regeneration that lead to chronic inflammation and muscle replacement by fibrofatty tissue. Our recent findings demonstrated that Resolvin-D2, a bioactive lipid derived from omega-3 fatty acids, has the capacity to dampen inflammation and stimulate muscle regeneration to alleviate disease progression. This therapeutic avenue has many advantages compared to glucocorticoids, the current gold-standard treatment for Duchenne Muscular Dystrophy. However, the use of bioactive lipids as therapeutic drugs also faces many technical challenges such as their instability and poor oral bioavailability.Methods: Here, we explored the potential of PSB-KD107, a synthetic agonist of the resolvin-D2 receptor Gpr18, as a therapeutic alternative for Duchenne Muscular Dystrophy.Results and discussion: We showed that PSB-KD107 can stimulate the myogenic capacity of patient iPSC-derived myoblasts in vitro. RNAseq analysis revealed an enrichment in biological processes related to fatty acid metabolism, lipid biosynthesis, small molecule biosynthesis, and steroid-related processes in PSB-KD107-treated mdx myoblasts, as well as signaling pathways such as Peroxisome proliferator-activated receptors, AMP-activated protein kinase, mammalian target of rapamycin, and sphingolipid signaling pathways. In vivo, the treatment of dystrophic mdx mice with PSB-KD107 resulted in reduced inflammation, enhanced myogenesis, and improved muscle function. The positive impact of PSB-KD107 on muscle function is similar to the one of Resolvin-D2. Overall, our findings provide a proof-of concept that synthetic analogs of bioactive lipid receptors hold therapeutic potential for the treatment of Duchenne Muscular Dystrophy

Pediatric data for normal distal femur bone mineral density in children aged 3 to 18 years using the lunar prodigy densitometer

Objectives: Children with compromised weight bearing and limited mobility due to neuromuscular impairments are particularly at risk for low trauma long bone fractures. Whilst dual-energy absorptiometry scan (DXA) is a useful tool to assess areal bone mineral density (aBMD) in children, several obstacles can impede proper assessment of whole body (WB) or lumbar spine (LS) aBMD in this population. Musculo-skeletal deformities and orthopaedic hardware can render measurement of aBMD at these sites uninterpretable or impossible. For example, measurement of LS aBMD in a child with a neuromuscular scoliosis may be technically infeasible and clinically invalid if orthopaedic hardware is located in the region of interest. The lateral distal femur (LDF) has been proposed as an alternative site for aBMD assessment. Furthermore, distal femur fractures are common in this population, making LDF aBMD assessment clinically relevant. There are few normative data for aBMD at the LDF in children. This study aimed to construct normative centile curves for LDF aBMD using data from healthy children aged 3-18 years using the Lunar Prodigy DXA scan. Methods: This was a cross-sectional assessment of 241 healthy Canadian children (48% males, near 89% Caucasian) ranging in age from 3-18 years. aBMD measures were completed at 3 different regions of the LDF ("region 3, 4 and 5"), LS and WB using the Lunar Prodigy Densitometer. Age was chosen as the scaling variable and sex-specific reference curves for each of the 3 LDF regions were generated using LMS-ChartMaker Pro. LDF aBMD-for-age Z-scores were calculated then compared to WB and LS aBMD and anthropometric data by correlation analysis. Linear regression and ANOVA studies were used to examine predictors associated with aBMD at the different LDF regions. Results: LDF aBMD measurements were progressively higher with older age (R2 = 0.64 Region 3; R2 = 0.77 region 4; R2 = 0.83 region 5; p-value < 0.0001 for all regions) and were highly correlated with height and weight (R2 ≥ 0.60, p-value &lt;0.0001or all regions). Furthermore, LDF aBMD was highly correlated with WB (R2 ≥ 0.74; p-value &lt;0.0001 for all regions) and LS aBMD measurements (R2 ≥ 0.71; p-value < 0.0001for all regions). LDF region 3 Z-scores correlated best with LS aBMD Z-scores (R2 = 0.36; p-value &lt; 0.0001) while region 5 Z-scores correlated best with WB aBMD Z-scores (R2 ≥ 0.41; p-value &lt; 0.0001). At each femoral region, sex differences in aBMD depended significantly on age (p-value for interaction ≤ 0.005).Conclusion: This is the first study to provide normative data for LDF aBMD in children between the ages of 3 and 18 years, using the Lunar Prodigy DXA scan.Objectifs : Les enfants qui ont une mobilité réduite secondaire à des maladies neuromusculaires sont à risque de subir des fractures ostéoporotiques. La densitométrie osseuse (DXA) est l'examen de dépistage de référence pour évaluer la densité osseuse (DO) chez l'enfant. Les contractures au niveau des membres inférieurs, une scoliose et du matériel orthopédique sont des obstacles à l'évaluation et l'interprétation de la DO dans certaines régions anatomiques, tel que la colonne et le fémur proximale. De plus, les fractures ostéoporotiques chez ces enfants siègent le plus souvent au niveau des membres inférieurs et particulièrement au niveau fémoral. Donc la DO du fémur distal demeure une zone anatomique cliniquement pertinente à évaluer Les données normatives pédiatriques de DO de la région fémorale distale latérale (FDL) sont peu nombreuses. Cette étude propose d'établir des normes pédiatriques de DO pour 3 régions du FDL pour les enfants entre 3-18 ans pour le densitomère de type LUNAR Prodigy. Méthodes: Il s'agit d'une étude de cohorte transversale incluant 241 enfants Canadiens en bonne santé (48% garçons, 89% Caucasiens) entre 3-18 ans. Les mesures de DO ont été récoltées dans 3 régions du FDL (région 3, 4 et 5), le corps entiers, le fémur proximal et la colonne lombaire. La technique de régression LMS-ChartMaker Pro est utilisée pour la construction de courbes normatives correspondantes à l'ensemble des données en fonction de l'âge et du sexe (Z-scores). Les corrélations entre la DO et les différentes régions du FDL et les autres zones anatomiques sont interprétées. Les études de corrélations entre la DO au niveau du FDL et les données anthropométriques ont été complétées pour estimer l'influence de ces facteurs sur la densité osseuse. Résultats : La DO du FDL croitre avec l'âge (R2 = 0.64 région 3; R2 = 0.77 région 4; R2 = 0.83 région 5; p-value &lt; 0.0001 pour toutes les régions) et était fortement corrélée avec la taille et le poids (R2 ≥ 0.60, p-value &lt; 0.0001 pour toutes les régions). De plus, la DO du FDL était fortement corrélée avec la DO au corps entier (R2 ≥ 0.74; p-value &lt;0.0001) et la colonne (R2 ≥ 0.71; p-value &lt; 0.0001). Les Z-scores de la densité osseuse de la région 3 du FDL corrèle le plus fortement aux mesures de la colonne (R2 = 0.36; p-value &lt; 0.0001). Cependant, les Z-scores de la région 5 corrèlent le plus fortement aux mesures du corps entier (R2 ≥ 0.41; p-value &lt; 0.0001). À chaque région du FDL, les mesures de DO entre les sexes diffèrent de façon significative selon l'âge (p-value pour l'interaction ≤ 0.005). Conclusion: Ceci est la première étude à décrire des normes pédiatriques de la DO du FDL pour le densitomètre Lunar Prodigy

Calvarial doughnut lesions with bone fragility in a French-Canadian family; case report and review of the literature

Calvarial Doughnut Lesions with Bone Fragility (CDL) is an autosomal dominant genetic disease, characterized by low bone mineral density, multiple fractures starting in childhood, and sclerotic doughnut-shaped lesions in the cranial bones. Aube and colleagues described in 1988 a French-Canadian family of 12 affected members who had a clinical diagnosis of doughnut lesions of the skull, with pathological fractures, osteopenia, "bone in bone" in the vertebral bodies and squaring of metatarsal and metacarpal bones. Herein we study new members of this family. Sequential genetic testing identified a nonsense variant c.148C>T, p. Arg50* in SGMS2 previously reported in other families. SGMS2 encodes Sphingomyelin Synthase 2, which produces Sphingomyelin (SM), a major lipid component of the plasma membrane that plays a role in bone mineralization. The nonsense variant is associated with milder phenotype. The proband presents with bone in bone vertebral appearance that had been defined uniquely in the first cases described in the same family. The proband's son was identified to carry the same variant, which makes him the sixth generation with the diagnosis of CDL. We also report that the same pathogenic variant was identified in another previously described family, from France. These reports further confirm the genetic basis of CDL, the recurrence of the same variant (p.Arg50*) in individuals of the same ancestry, and the variable penetrance of some of the clinical findings.Peer reviewe