Aim: 

Malignant Hyperthermia (MH) and Central Core Disease (CCD) are related skeletal muscle diseases often linked to mutations in the ryanodine receptor (RYR1) gene, the Ca2+ release channel of sarcoplasmic reticulum (SR). Expression of the RYR1Y522S/WT mutation (associated in humans to MH susceptibility with cores) in mice causes SR Ca2+ leak, excessive production of reactive species (RS), and MH.

Methods: 

Here we investigated weather RYR1Y522S/WT mice also develop CCD and which are the steps leading to core formation in muscle.

Results: 

We discovered that mitochondrial swelling/disruption is the first detectable change in 2 months old fibers. Damage to these organelles is followed by local disruption of nearby SR, T-tubules, and contractile elements, which generates early cores. At later stages (1 year of age) regions of delimited myofibril contractures, characterized by complete lack of mitochondria and SR (contracture cores), and regions in which contractile elements are severely compromised (unstructured cores) become very frequent.

Conclusion: 

We suggest that initial mitochondrial and SR disruption in early cores is initiated by the abnormal Ca2+ leak through the mutated RYR1 and/or by excessive amount of RS. Subsequent loss of SR and mitochondria Ca2+ sequestration results in the formation of contracture cores and possibly activation of the proteolytic machinery leading to unstructured cores.