Assessment of myogenic potency in patient-derived fibroblasts with c.1289-2A>G Desmin mutation

Abstract

Abstract Objectives The ultra-rare DES c.1289-2A>G mutation, resulting in a 48-base pair insertion in the Desmin tail domain, is associated with late-onset MFM1 (myofibrillar myopathy-1; OMIM number; 601419) and exhibits distinctive pathological features. Despite sustained expression and cytoskeletal integrity, muscle biopsies reveal dystrophic characteristics through an unidentified mechanism. A deeper understanding of the molecular mechanisms underlying Desmin-related MFM1 could enhance our perspective and comprehension of the disease’s pathophysiology. In this study, we aimed to investigate the pathological phenotype by assessing the myogenic potency of MyoD-induced patient-derived fibroblasts. Methods Following the immortalization and myoconversion of unaffected and patient-derived fibroblast cells, we analyzed the myogenic potency of the mutant and control groups on day 5 post-differentiation. This analysis involved staining cells with MF20 antibody and DAPI after MyoD induction. Results Employing six parameters to quantify extra nuclei and myotube properties, we unveil impaired myogenic differentiation in c.1289-2A>G mutant cells, as evidenced by a compromised fusion index and distinctive myogenic features. In summary, our preliminary findings indicate phenotypic abnormalities and suggest an association between the DES c.1289-2A>G mutation and delayed maturation and MFM in affected individuals. Conclusions Our results indicate a significant involvement of Desmin in the myogenic maturation of muscle cells. Further investigation is required to understand the changes in the transcriptome during the myoconversion of patient-derived fibroblasts.