Abstract
Filamin C (FLNc) is mainly expressed in striated muscle cells where it localizes to Z-discs, myotendinous junctions and intercalated discs. Recent studies have revealed numerous mutations in the FLNC gene causing familial and sporadic myopathies and cardiomyopathies with marked clinical variability. The most frequent myopathic mutation, p.W2710X, which is associated with myofibrillar myopathy, deletes the carboxy-terminal 16 amino acids from FLNc and abolishes the dimerization property of Ig-like domain 24. We previously characterized “knock-in” mice heterozygous for this mutation (p.W2711X), and have now investigated homozygous mice using protein and mRNA expression analyses, mass spectrometry, and extensive immunolocalization and ultrastructural studies. Although the latter mice display a relatively mild myopathy under normal conditions, our analyses identified major mechanisms causing the pathophysiology of this disease: in comparison to wildtype animals (i) the expression level of FLNc protein is drastically reduced; (ii) mutant FLNc is relocalized from Z-discs to particularly mechanically strained parts of muscle cells, i.e. myotendinous junctions and myofibrillar lesions; (iii) the number of lesions is greatly increased and these lesions lack Bcl2-associated athanogene 3 (BAG3) protein; (iv) the expression of heat shock protein beta-7 (HSPB7) is almost completely abolished. These findings indicate grave disturbances of BAG3-dependent and -independent autophagy pathways that are required for efficient lesion repair. In addition, our studies reveal general mechanisms of lesion formation and demonstrate that defective FLNc dimerization via its carboxy-terminal domain does not disturb assembly and basic function of myofibrils. An alternative, more amino-terminally located dimerization site might compensate for that loss. Since filamins function as stress sensors, our data further substantiate that FLNc is important for mechanosensing in the context of Z-disc stabilization and maintenance.
Highlights
Heterozygous mutations in the human filamin C gene (FLNC) located on chromosome 7q32 cause hereditary and sporadic myopathies and cardiomyopathies with marked phenotypic variability [18, 23, 32, 86]
Filamin C is expressed at high levels in the soleus muscle of mice To determine which striated muscles express the highest FLNc levels, protein extracts from different skeletal muscles and the heart from WT mice were analyzed by western blotting
Comparison of the expression levels of filamin C mRNA and protein in WT and Hom mice Reverse transcription quantitative polymerase chain reaction (RT-qPCR) to analyze Flnc mRNA expression revealed no significant differences between total Flnc mRNA levels in the soleus muscles of WT and Hom animals (Fig. 1b)
Summary
Heterozygous mutations in the human filamin C gene (FLNC) located on chromosome 7q32 cause hereditary and sporadic myopathies and cardiomyopathies with marked phenotypic variability [18, 23, 32, 86]. The first disease-causing FLNC mutations were described in the context of skeletal myopathies displaying the classical features of myofibrillar myopathies (MFMs; MIM# 609524), which are morphologically characterized by sarcoplasmic protein aggregates and degenerative changes of the myofibrillar apparatus [23, 67, 69, 86]. FLNC mutations were subsequently demonstrated to cause distal myopathies (MIM# 614065) without evidence for protein aggregation [16, 26]. A growing number of truncating and missense FLNC mutations have been identified in cardiac diseases comprising restrictive, hypertrophic, dilated and arrhythmogenic cardiomyopathies (MIM# 617047) [4, 5, 9, 18, 25, 56, 78]. A large part of those are associated with skeletal myopathies and cardiomyopathies [83]
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