Aartsma-Rus, A. | Search bioRxiv

bioRxiv2023

The vitamin B3 analogue nicotinamide riboside has only very minor effects on reducing muscle damage in mdx mice

BACKGROUNDVitamin B3 analogue nicotinamide riboside (NR) has been suggested to have beneficial effects on muscle pathology in a mouse model for Duchenne muscular dystrophy (DMD). In muscle dystrophy, NR is thought to act acts by increasing levels of NAD+, to improve mitochondrial functioning and reduce muscle pathology. OBJECTIVEWe here aimed to validate the effects of NR to improve muscle quality after eight weeks of treatment in two different mouse models for DMD: the commonly used mdx mouse on a C57BL/10 background (BL10mdx) and the more severely affected mdx mouse on a DBA/2J background (D2-mdx). METHODSTo study in more detail whether NR treatment had an impact on muscle pathology, we assessed the expression levels of several markers for DMD pathology (fibrosis, regeneration and inflammation) in diaphragm. RESULTSOur data showed a trend for increase in NAD+-levels in blood; only in the D2-mdx NR-treated mice the NAD+-levels were slightly increased. These markers were elevated in mdx models compared to controls, but not affected by the NR treatment. Histological analysis of muscle tissues indicated a mild treatment effect in D2-mdx mice. CONCLUSIONSBased on our results, testing NR treatment in clinical trials in DMD patients is not warranted.

genetics↗

bioRxiv2022

Spatial transcriptomics reveal markers of histopathological changes in Duchenne muscular dystrophy mouse models

Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene, leading to lack of dystrophin. Chronic muscle damage eventually leads to histological alterations in skeletal muscles. The identification of genes and cell types driving tissue remodeling is a key step to develop effective therapies. Here we use spatial transcriptomics in two DMD mouse models differing in disease severity to identify gene expression signatures underlying skeletal muscle pathologies and directly link this to the muscle histology. Deconvolution analysis allowed the identification of cell types contributing to histological alterations. We show how the expression of specific genes is enriched in areas of muscle regeneration (Myl4, Sparc, Hspg2), fibrosis (Vim, Fn1, Thbs4) and calcification (Bgn, Ctsk, Spp1). Finally, our analysis of differentiation dynamics in the severely affected D2-mdx muscle shows a subset of the muscle fibers are predicted to become affected in its future state. Genes associated with tissue remodeling could enable to design new diagnostic and therapeutic strategies for DMD.

genomics↗