Myofibrillar instability exacerbated by acute exercise in filaminopathy

Abstract

Filamin C (FLNC) mutations in humans cause myofibrillar myopathy (MFM) and cardiomyopathy, characterized by protein aggregation and myofibrillar degeneration. We generated the first patient-mimicking knock-in mouse harbouring the most common disease-causing filamin C mutation (p.W2710X). These heterozygous mice developed muscle weakness and myofibrillar instability, with formation of filamin C- and Xin-positive lesions streaming between Z-discs. These lesions, which are distinct from the classical MFM protein aggregates by their morphology and filamentous appearance, were greatly increased in number upon acute physical exercise in the mice. This pathology suggests that mutant filamin influences the mechanical stability of myofibrillar Z-discs, explaining the muscle weakness in mice and humans. Re-evaluation of biopsies from MFM-filaminopathy patients with different FLNC mutations revealed a similar, previously unreported lesion pathology, in addition to the classical protein aggregates, and suggested that structures previously interpreted as aggregates may be in part sarcomeric lesions. We postulate that these lesions define preclinical disease stages, preceding the formation of protein aggregates.

FLNC Gene Splice Mutations Cause Dilated Cardiomyopathy

“…Our data, together with two DCM population screenings (49, 50), the study of other cardiomyopathies (HCM and restrictive) (13, 14), and previous data on MFM (4, 10, 12, 33, 34), suggest that FLNC rare variants can cause a spectrum of cardiac and skeletal muscle phenotypes. Finally, studies in vivo (mice, zebrafish and medaka fish) (24, 47, 51) further support our findings that suggest FLNC mutations can lead to sarcomeric structural changes and ultimately cause cardiac dysfunction.…”

“…The ultrastructural phenotypes observed in zebrafish flncb +p53 MO cardiomyocytes share certain commonalities with skeletal muscle phenotypes observed in knock-in mice heterozygous for a patient mimicking a filamin C mutation (47), including the dissolution of z-discs and presence of possible autophagic vesicles. However, differences are also apparent.…”

Deficiency in Kelch protein Klhl31 causes congenital myopathy in mice

“…Consistent with these findings, in the presence of the mutant K48R Ub, we observed an intense band at the appropriate size of FlnC with diminished polyubiquitination, suggesting FlnC is ubiquitinated but cannot polymerize the K48-linked Ub chain required for proteasomal degradation ( Figure 6B). In addition, we were able to detect large FlnC aggregates in Klhl31-KO skeletal muscle (Figure 6C), which is also observed in both humans and mouse models of FlnC myopathies (33,34). Given that Klhl31 interacts with FlnC and not Slmap or Usmg5, it is likely that the primary defect in Klhl31-KO mice is Z-disc instability due to accumulation of FlnC and that the upregulation of Slmap and Usmg5 is secondary.…”

Mutant desmin substantially perturbs mitochondrial morphology, function and maintenance in skeletal muscle tissue

“…This difference suggests that additional factors are needed to unveil the typical disease pathology in heterozygous R349P desmin knock-in mice. Accordingly, acute and strenuous physical exercise has recently been shown to markedly accentuate the muscle fiber pathology in heterozygous W2711X filamin-C knock-in mice, which are a patient-mimicking model of filamin-C related myofibrillar myopathy [12]. Future exercise studies with the heterozygous R349P desmin knock-in mice will address the issue whether an acute energy demand accelerates the general muscle pathology and increases the degree of mitochondrial pathology.…”