FOR 1228: Molecular Pathogenesis of Myofibrillar Myopathies
Final Report Abstract
Myofibrillar myopathies (MFM) comprise hereditary and sporadic protein aggregate myopathies of considerable clinical and genetic heterogeneity. Signs of myofibrillar degeneration and Desmin-positive sarcoplasmic protein aggregates are the pathomorphological denominators of all MFM. To date, no specific therapy is availiable for this progressive and often lethal group of muscle diseases. The aim of FOR1228 was to decipher central aspects of the molecular pathogenesis of MFM. In keeping with the formulated goals of the two granted funding periods, FOR1228 has provided a plethora of substantial contributions addressing 1) the characterization of individual and shared disease mechanisms in MFM due to pathogenic desmin-, plectin-, filamin C-, VCP- and FHL1-mutations, 2) systematic analyses of disease-specific cell and animal models, 3) the validation of cell and animal models for pharmacological treatment strategies, 4) the proteomic characterization of the composition of pathological protein aggregates in skeletal muscle biopsies from patients with genetically proven MFM-causing gene mutations and mouse models, 5) the identification of novel candidate genes causing human MFM by laser microdissection followed by proteomic analysis and genomic DNA sequencing, as well as 6) biomechanical properties of MFM in myoblasts, myofibers and whole muscles. The most outstanding scientific achievements of FOR1228 have been i) the delineation of central, disease-specific mechanisms in desmin-, plectin- and filamin C-related MFM; ii) a multilevel characterization of the clinical, morphological, functional and molecular effects inflicted by the expression of mutant desmin-, plectin-, filamin C, VCP and FHL1; iii) the adaptation and refinement of laser-microdissection in conjunction with proteomic analysis to study normal and diseased skeletal muscle tissue; iv) the proteomic characterization of pathological protein aggregates in more than 100 human MFM skeletal muscle biopsies; v) the generation and characterization of the first truly patientmimicking knock-in and knock-out mouse and cell models for desmin-, plectin- and filamin C-related MFM; vi) the preclinical evaluation of the chemical chaperone 4-phenyl-butyric-acid (4-PBA) as a promising drug treatment approach for plectinopathies and other forms of MFM; vii) the preclinal evaluation of adeno-associated virus 9-mediated gene transfer of wild-type desmin cDNA as a curative treatment approach for cardiomyopathies in autosomal-recessive desminopathies with a complete lack of desmin protein expression. The successful collaborative work of FOR1228 is highlighted by a high number of publications in refereed international scientific journals, scientific prizes awarded to several junior and senior members of this consortium, the promotion of four principal investigators to full professorship positions as well as the formation and consolidation of interdisciplinary muscle research teams at the Ruhr-University Bochum and the Friedrich-Alexander-University Erlangen-Nuremberg. Taken together, FOR1228 - with its high level of international visability - has provided invaluable contributions to our current understanding of the clinical, genetic, myopathological, biochemical and biomechanical aspects of MFM. Through the creation of the first truly patient-mimicking mouse and cell models in combination with our successful preclinical drug and AAV9-mediated gene replacement studies, FOR1228 also paved the way to novel targeted treatment concepts for MFM.
