Paradas, C. | bioRxiv Science

bioRxiv2024

The glycosyltransferase POGLUT1 regulates muscle stem cell development and maintenance in mice

Mutations in protein O-glucosyltransferase 1 (POGLUT1) cause a recessive form of limb-girdle muscular dystrophy (LGMD-R21) associated with reduced satellite cell number and NOTCH1 signaling in adult patient muscles and impaired myogenic capacity of patient-derived muscle progenitors. However, the in vivo roles of POGLUT1 in the development, function, and maintenance of satellite cells are not well understood. Here, we show that conditional deletion of mouse Poglut1 in myogenic progenitors leads to early lethality, postnatal muscle growth defects, reduced Pax7 expression, abnormality in muscle extracellular matrix, and impaired muscle repair. Poglut1-deficient muscle progenitors exhibit reduced proliferation, enhanced differentiation, and accelerated fusion into myofibers. Inducible loss of Poglut1 in adult satellite cells leads to their precocious differentiation and impairs muscle repair upon serial injury. Cell-based signaling assays and mass spectrometric analysis indicate that POGLUT1 is required for the activation of NOTCH1, NOTCH2, and NOTCH3 in myoblasts and that NOTCH3 is a target of POGLUT1 like NOTCH1 and NOTCH2. These observations provide insight into the roles of POGLUT1 in muscle development and repair and the pathophysiology of LGMD-R21.

developmental biology↗

bioRxiv2024

Computational analysis of SOD1-G93A mouse muscle biomarkers for comprehensive assessment of ALS progression

AimsTo identify potential image biomarkers of neuromuscular disease by analysing morphological and network-derived features in skeletal muscle biopsies from a murine model of amyotrophic lateral sclerosis (ALS), the SOD1G93A mouse, and wild-type (WT) controls at distinct stages of disease progression. MethodsUsing the NDICIA computational framework, we quantitatively evaluated histological differences between skeletal muscle biopsies from SOD1G93A and WT mice. The process involved the selection of a subset of features revealing these differences. A subset of discriminative features was selected to characterise these differences, and their temporal dynamics were assessed across disease stages. ResultsOur findings demonstrated that muscle pathology in the mutant model evolves from early alterations in muscle fibre arrangement, detectable at the presymptomatic stage through graph theory features, to the subsequent development of the typical morphological pattern of neurogenic atrophy at more advanced disease stages. ConclusionsOur assay identifies a neurogenic signature in mutant muscle biopsies, even when the disease was phenotypically imperceptible. KEY POINTS- NDICIA analysis detected differences between SOD1G93A and WT muscles at presymptomatic stage through the analysis of graph theory features. - Our computational tool identified different neurogenic-like traits in the ALS mouse model at all analysed stages of disease progression. - Differences between SOD1G93A and WT muscle images became more pronounced as the disease advanced. - The integration of UMAP into the upgraded NDICIA framework was validated as a robust alternative to PCA. - Muscle fibre characteristics in SOD1WT closely resembled those of WT mice.

neuroscience↗