Abstract
ABSTRACTThe core myopathies are a group of congenital myopathies with variable clinical expression – ranging from early-onset skeletal-muscle weakness to later-onset disease of variable severity – that are identified by characteristic ‘core-like’ lesions in myofibers and the presence of hypothonia and slowly or rather non-progressive muscle weakness. The genetic causes are diverse; central core disease is most often caused by mutations in ryanodine receptor 1 (RYR1), whereas multi-minicore disease is linked to pathogenic variants of several genes, including selenoprotein N (SELENON), RYR1 and titin (TTN). Understanding the mechanisms that drive core development and muscle weakness remains challenging due to the diversity of the excitation-contraction coupling (ECC) proteins involved and the differential effects of mutations across proteins. Because of this, the use of representative models expressing a mature ECC apparatus is crucial. Animal models have facilitated the identification of disease progression mechanisms for some mutations and have provided evidence to help explain genotype-phenotype correlations. However, many unanswered questions remain about the common and divergent pathological mechanisms that drive disease progression, and these mechanisms need to be understood in order to identify therapeutic targets. Several new transgenic animals have been described recently, expanding the spectrum of core myopathy models, including mice with patient-specific mutations. Furthermore, recent developments in 3D tissue engineering are expected to enable the study of core myopathy disease progression and the effects of potential therapeutic interventions in the context of human cells. In this Review, we summarize the current landscape of core myopathy models, and assess the hurdles and opportunities of future modeling strategies.
Highlights
The core myopathies are the most prevalent subgroup of congenital myopathies (Amburgey et al, 2011; Gonorazky et al, 2018; Maggi et al, 2013; Norwood et al, 2009), comprising central core disease (CCD; Box 1) and multi-minicore disease (MmD; Box 2)
The genetic variants causing core myopathies primarily affect proteins involved in skeletal-muscle excitation-contraction coupling (ECC; see Box 3 for a glossary of terms; Fig. 1), either by altering calcium ion (Ca2+) transits between the sarcoplasmic reticulum (SR) and sarcoplasm (Box 3), or by disrupting the structure of the sarcomere (Box 3; Fig. 2)
As mutations in a single gene can result in multiple forms of congenital myopathy, it is likely that the protein dysfunction differs too
Summary
The core myopathies are the most prevalent subgroup of congenital myopathies (Amburgey et al, 2011; Gonorazky et al, 2018; Maggi et al, 2013; Norwood et al, 2009), comprising central core disease (CCD; Box 1) and multi-minicore disease (MmD; Box 2). All muscles assessed (FDB, EDL+soleus) were affected, core severity increases with age Structural abnormalities observed only in male Ryr1T4826I/T4826I soleus from 12 months (not EDL): accumulation of amorphous, electron-dense material at the myofiber periphery with associated T-tubule honeycomb networks.
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