Myofibrillar Myopathies: New Perspectives from Animal Models to Potential Therapeutic Approaches

Abstract

Myofibrillar myopathies (MFMs) are muscular disorders involving proteins that play a role in the structure, maintenance processes and protein quality control mechanisms closely related to the Z-disc in the muscular fibers. MFMs share common histological characteristics including progressive disorganization of the interfibrillar network and protein aggregation. Currently no treatment is available. In this review, we describe first clinical symptoms associated with mutations of the six genes (DES, CRYAB, MYOT, ZASP, FLNC and BAG3) primary involved in MFM and defining the origin of this pathology. As mechanisms determining the aetiology of the disease remain unclear yet, several research teams have developed animal models from invertebrates to mammalians species. Thus we describe here these different models that often recapitulate human clinical symptoms. Therefore they are very useful for deeper studies to understand early molecular and progressive mechanisms determining the pathology. Finally in the last part, we emphasize on the potential therapeutic approaches for MFM that could be conducted in the future. In conclusion, this review offers a link from patients to future therapy through the use of MFMs animal models.

Keywords: MFM animal models; Myofibrillar myopathies; therapeutics.

Fig.1

Clinical overview of MFM alterations. Each color represent the features found in one pathology. Legend color is detailed in the box localized in up right corner. The text in italic correspond to specific pattern visualized in MRI studies. Alpha-B-crystallinopathies shares common features with desmin. So only specific pattern of alpha-B-crystallinopathies are indicated.

Fig.2

Altered desmin subcellular distribution in skeletal muscle tissue. A- 11-week-old mice (C57bl6J) were injected in tibialis anterior (TA) with associated-adeno-virus (AAV) encoding Myc-tagged wild-type (WT) or D399Y desmin. One month later, TA were extracted and frozen, and Myc immunostaining on transverse or longitudinal cryosections was performed to detect exogenous desmin. D399Y shows a perinuclear accumulation related to human desmin aggregation observed in patients. Scale bar = 20 μm. B- DesKI-R405W mice (homologous to R406W mutation in human, C57bl6N) were analyzed at 3 months old. Briefly, TA were extracted and frozen and desmin immunostaining was performed on transverse or longitudinal cryosections to detect endogenous desmin in homozygous (Hom), heterozygous (Het) or wild-type (WT) mice. A typical desminopathy staining pattern with predominantly subsarcolemmal and also sarcoplasmic desmin-positive protein aggregates can be observed in homozygous tissue. Moreover, a regular cross-striated desmin pattern is present in WT mice, and mainly preserved in HET mice, whereas Hom mice show an altered striation and fiber shapes. Scale bar = 20 μm.

Fig.3

Scheme of dysregulated functions in myofibrillar myopathies and potential therapeutic treatments.