Abstract-Text (inkl. Referenzen)

Background: Filaminopathies represent a subgroup of myofibrillar myopathies MFM which in turn belong to a heterogenous group of neuromuscular disorders. MFM are genetically caused and result in muscle weakness, probably due to protein aggregation from the Z-disk in striated muscle fibers. More than 100 different mutations of filamin C (FLNC) have been reported. However, the mechanism of the disease is not yet fully elucidated. Developing in vitro models for neuromuscular diseases is not only beneficial for the basic understanding of the disease but also provides a tool to screen therapeutic agents and gene therapeutic approaches. This work aims to create cell culture models for a new FLNC variant, p.[Q1662X]

Methods: Three different approaches were applied: (i) immortalization of the primary muscle cells of the patient by inducing hTERT and CDK4 expression with lentiviral vectors, (ii) transdifferentiating the primary fibroblasts to myoblasts by forced expression of MyoD and (iii) inducing pluripotency in the diseased fibroblast and differentiating them in a 3D model to obtain pure muscle-like cells.

Results: The forementioned lines were established. All three approaches can differentiate into multinucleated myotubes with variance in the efficiency.

Conclusions: We present FLNC in vitro models for further pathophysiological studies and addressing innovative treatment options.