Muscle fibre mitochondrial [Ca 2+ ] dynamics during Ca 2+ waves in RYR1 gain-of-function mouse

• Published in: Acta Physiologica Vol. 240; no. 3; p. e14098
• Main Authors: Gaglianone, Rhayanna B, Launikonis, Bradley S
• Format: Journal Article
• Language: English
• Published: England 01.03.2024
• Subjects: Adenosine Triphosphate - metabolism; Animals; Gain of Function Mutation; Mice; Mitochondria; Muscle Fibers, Skeletal - metabolism; Ryanodine Receptor Calcium Release Channel - metabolism; ryanodine receptor; skeletal muscle; Ca2; confocal; malignant hyperthermia; mitochondria
• ISSN: 1748-1708; 1748-1716
• DOI: 10.1111/apha.14098

A fraction of the Ca released from the sarcoplasmic reticulum (SR) enters mitochondria to transiently increase its [Ca ] ([Ca ] ). This transient [Ca ] increase may be important in the resynthesis of ATP and other processes. The resynthesis of ATP in the mitochondria generates heat that can lead to hypermetabolic reactions in muscle with ryanodine receptor 1 (RyR1) variants during the cyclic releasing of SR Ca in the presence of a RyR1 agonist. We aimed to analyse whether the mitochondria of RYR1 variant muscle handles Ca differently from healthy muscle. We used confocal microscopy to track mitochondrial and cytoplasmic Ca with fluorescent dyes simultaneously during caffeine-induced Ca waves in extensor digitorum longus muscle fibres from healthy mice and mice heterozygous (HET) for a malignant hyperthermia-causative RYR1 variant. Mitochondrial Ca -transient peaks trailed the peak of cytoplasmic Ca transients by many seconds with [Ca ] not increasing by more than 250 nM. A strong linear relationship between cytoplasmic Ca and [Ca ] amplitudes was observed in HET RYR1 KI fibres but not wild type (WT). Our results indicate that [Ca ] change within the nM range during SR Ca release. HET fibre mitochondria are more sensitive to SR Ca release flux than WT. This may indicate post-translation modification differences of the mitochondrial Ca uniporter between the genotypes.