Characterization and temporal development of cores in a mouse model of malignant hyperthermia

Abstract

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 Ca 2؉ 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 (RYR1 Y522S/WT ), the mutation causes SR Ca 2؉ leak and MHS. Here, we identified mitochondrial-deficient core regions in skeletal muscle fibers from RYR1 Y522S/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 RYR1 Y522S/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 RYR1 Y522S/WT mice: Initial mitochondrial/SR disruption in confined areas causes significant loss of local Ca 2؉ sequestration that eventually results in the formation of contractures and progressive degradation of the contractile elements.central core disease ͉ excitation-contraction coupling ͉ muscle disease ͉ ryanodine receptor ͉ mitochondria

Interactions between sarco-endoplasmic reticulum and mitochondria in cardiac and skeletal muscle – pivotal roles in Ca2+ and reactive oxygen species signaling

“…Notably, the distribution of mitochondria in mouse skeletal muscle changes during development, from a longitudinal arrangement towards a triad-adjacent location running in parallel to the z-lines. In parallel, the frequency of tethers increases during the first four postnatal months (Boncompagni et al, 2009). Furthermore, there are extensive associations between SR and mitochondria in mammalian muscle, whereas lower vertebrates display a less-extensive interface (Franzini-Armstrong and Boncompagni, 2011).…”

“…These changes are accompanied by severely damaged and enlarged mitochondria (Durham et al, 2008). The mice present disrupted mitochondria early in development and muscles with extended contracture areas that lack SR or mitochondria (at two months of age) (Boncompagni et al, 2009). In another knock-in mouse model of MH, RyR1(R163C), bioenergetics defects, including elevated [Ca 2+ ] m and ROS, and decreased oxidative phosphorylation have been reported (Giulivi et al, 2011).…”

“…Tethers have been observed in the muscle between mitochondria and jSR or network SR (nSR), and less frequently TTs (Boncompagni et al, 2009;Hayashi et al, 2009). The role of MFN2 in tethering is currently debated since in MFN2-ablated heart, both unaltered SR-mitochondrial associations (Papanicolaou et al, 2011) and structural derangements have been reported.…”

Increased mitochondrial nanotunneling activity, induced by calcium imbalance, affects intermitochondrial matrix exchanges

“…The cardiac ryanodine receptor (RyR2) is the SR Ca 2+ release channel involved in normal excitation-contraction (E-C) coupling in cardiac muscle. Mutations in skeletal ryanodine receptor (RyR1) resulting in unbalanced Ca 2+ homeostasis can affect mitochondrial morphology and distribution (22,23). Defects in mitochondrial dynamics and mitochondrial morphology have also been reported in various cardiomyopathies and heart failure but have not been linked to Ca 2+ homeostasis.…”

Gene Dose Influences Cellular and Calcium Channel Dysregulation in Heterozygous and Homozygous T4826I-RYR1 Malignant Hyperthermia-susceptible Muscle

“…Both mouse models have contributed valuable information about how N-terminal mutations affect basal RYR1 channel dysfunction and alter pharmacological responses of intact muscle cells (19,20). Y522S-RYR1 mice show temporal development of skeletal muscle lesions resembling central core disease in humans (21), whereas Het R163C-RYR1 mice appear to have minimal muscle pathology. 4 These observations in mice are not consistent with clinical evidence indicating that both analogous mutations cause MH susceptibility in humans and that both are associated with central core disease, although the onset and patterns of muscle damage can differ (7,22).…”