Differential Sensitivity to Halothane Among Subgroups of Malignant Hyperthermia Susceptible Patients: Insights into Dual Pathophysiological Mechanisms

The pathophysiology of Malignant Hyperthermia Susceptibility (MHS) involves abnormal calcium release from the skeletal muscle’s sarcoplasmic reticulum. MHS diagnosis relies on either presence a pathogenic genetic variant in RYR1, CACNA1S, or STAC3, positive vitro caffeine-halothane contracture testing (CHCT). Muscle strips 65% 93 patients diagnosed as by CHCT our clinic developed excessive force response to halothane but not caffeine (named halothane–hypersensitive, HH). We recently reported HH patients, pathophysiological features that separate them those hyperreactive both agonists, named HS (Figueroa et al., 2019). Hallmarks individuals include higher incidence musculoskeletal symptoms and abnormalities homeostasis signaling myotubes derived their muscles. Here we extend clinical observations cell-level studies larger group measurement sensitivity primary myotubes. First, validate cellular approach comparing patients’ biopsied muscle with cultured same Then describe concentration dependence myotube halothane. While single concentration, myotubes’ reactions entire range uncover critical difference between two groups (HH HS) MH susceptible patients. Whereas have stronger responses halothane, sensitivity. results reveal mechanistic differences pathogenesis cells’ examination gauge altered mechanisms adult Supported grant AR071381 NIAMS/NIH.