The 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.