Characterization and temporal development of cores in a mouse model of malignant hyperthermia
2009
Boncompagni, Simona | Rossi, Ann E. | Micaroni, Massimo | Hamilton, Susan L. | Dirksen, Robert T. | Franzini-Armstrong, Clara | Protasi, Feliciano
Malignant hyperthermia (MH) and central core disease are related skeletal muscle diseases often linked to mutations in the type 1 ryanodine receptor (RYR1) gene, encoding for the Ca²⁺ release channel of the sarcoplasmic reticulum (SR). In humans, the Y522S RYR1 mutation is associated with malignant hyperthermia susceptibility (MHS) and the presence in skeletal muscle fibers of core regions that lack mitochondria. In heterozygous Y522S knock-in mice (RYR1Y⁵²²S/WT), the mutation causes SR Ca²⁺ leak and MHS. Here, we identified mitochondrial-deficient core regions in skeletal muscle fibers from RYR1Y⁵²²S/WT knock-in mice and characterized the structural and temporal aspects involved in their formation. Mitochondrial swelling/disruption, the initial detectable structural change observed in young-adult RYR1Y⁵²²S/WT mice (2 months), does not occur randomly but rather is confined to discrete areas termed presumptive cores. This localized mitochondrial damage is followed by local disruption/loss of nearby SR and transverse tubules, resulting in early cores (2-4 months) and small contracture cores characterized by extreme sarcomere shortening and lack of mitochondria. At later stages (1 year), contracture cores are extended, frequent, and accompanied by areas in which contractile elements are also severely compromised (unstructured cores). Based on these observations, we propose a possible series of events leading to core formation in skeletal muscle fibers of RYR1Y⁵²²S/WT mice: Initial mitochondrial/SR disruption in confined areas causes significant loss of local Ca²⁺ sequestration that eventually results in the formation of contractures and progressive degradation of the contractile elements.
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