An Association between OXPHOS-Related Gene Expression and Malignant Hyperthermia Susceptibility in Human Skeletal Muscle Biopsies

• Published in: International journal of molecular sciences Vol. 25; no. 6; p. 3489
• Main Authors: Chang, Leon, Motley, Rebecca, Daly, Catherine L, Diggle, Christine P, Hopkins, Philip M, Shaw, Marie-Anne
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.03.2024; MDPI
• Subjects: Biopsy; Caffeine; Calcium - metabolism; Carrier Proteins - metabolism; Disease susceptibility; Disease Susceptibility - metabolism; Fatty acids; Fever; Gene Expression; Genes; Genetic aspects; Genetics; Genotype & phenotype; Halothane - metabolism; Halothane - pharmacology; Humans; Hyperthermia; Instrument industry; International economic relations; Males; Malignant hyperthermia; Malignant Hyperthermia - genetics; Malignant Hyperthermia - metabolism; Metabolism; mitochondria; Muscle Contraction; Muscle, Skeletal - metabolism; Muscles; Musculoskeletal system; Ontology; Oxidative Phosphorylation; Phosphorylation; RNA sequencing; Ryanodine Receptor Calcium Release Channel - genetics; Ryanodine Receptor Calcium Release Channel - metabolism; skeletal muscle; Type 2 diabetes; United States; United Kingdom; United Kingdom > UK; RNA sequencing; skeletal muscle; malignant hyperthermia; mitochondria; gene expression; oxidative phosphorylation
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25063489

Malignant hyperthermia (MH) is a pharmacogenetic condition of skeletal muscle that manifests in hypermetabolic responses upon exposure to volatile anaesthetics. This condition is caused primarily by pathogenic variants in the calcium-release channel RYR1, which disrupts calcium signalling in skeletal muscle. However, our understanding of MH genetics is incomplete, with no variant identified in a significant number of cases and considerable phenotype diversity. In this study, we applied a transcriptomic approach to investigate the genome-wide gene expression in MH-susceptible cases using muscle biopsies taken for diagnostic testing. Baseline comparisons between muscle from MH-susceptible individuals (MHS, = 8) and non-susceptible controls (MHN, = 4) identified 822 differentially expressed genes (203 upregulated and 619 downregulated) with significant enrichment in genes associated with oxidative phosphorylation (OXPHOS) and fatty acid metabolism. Investigations of 10 OXPHOS target genes in a larger cohort (MHN: = 36; MHS: = 36) validated the reduced expression of and in MHS samples, but the remaining 8 selected were not statistically significant. Further analysis also identified evidence of a sex-linked effect in and expression, and a difference in expression across individuals with MH sub-phenotypes (trigger from in vitro halothane exposure only, MHS ( = 4); trigger to both in vitro halothane and caffeine exposure, MHS ( = 4)). Our data support a link between MH-susceptibility and dysregulated gene expression associated with mitochondrial bioenergetics, which we speculate plays a role in the phenotypic variability observed within MH.