%0 Journal Article
%T Abnormal Glucose Metabolism and Calcium Signaling in Malignant Hyperthermia (MHS) Patients
%J -
%D 2019
%R https://doi.org/10.1016/j.bpj.2018.11.2083
%X 40% of 367 patients diagnosed as MHS by the caffeine-halothane test were hyperglycemic (by fasting glucose or glycated Hb; Altamirano et al., BJA 2018). Their average age was 56.9 years (SD=11). Among 121 patients tested recently (Figueroa, BJA 2018 and this meeting), most patients hypersensitive to halothane but not caffeine (the ¡°HH¡±) had greater calcium signaling alterations than patients hypersensitive to both agonists. These patients were young (35.0 years average) and not diabetic. Membrane fractions of muscle biopsies from HH patients, studied by Coomassie stain, mass spectrometry and immunoblotting, had a 100% increased content of glycogenolytic enzymes: Glycogen Phosphorylase (GP) and Glycogen Debranching Enzyme (N=7 reference and 7 HH patients£¿). Total GP was unchanged in whole muscle (N=11, 13). The active form, GPa, was increased by 25%, and PHKA1, which phosphorylates inactive GP to GPa, was also increased in muscle and membrane fractions (N=7£¿). GP is concentrated near the Z disk in controls but displaced bilaterally in patients hypersensitive to halothane, to near overlap with RyR (in SR terminal cisternae). Phosphorylated glycogen synthase (pGS) was increased and its kinase 3 (pGSK3) decreased by¡«50% (N=7£¿), indicating reduced gylcogenesis. Consistent with the enzyme changes, HH patients had membrane-associated glycogen reduced >50 % (N=7£¿). Transporter GLUT4 was decreased by 30%£¿ in the membrane fraction, indicating upstream deficits in the glucose uptake pathway. Given the alterations in calcium signaling demonstrated in halothane hypersensitive patients (Figueroa 2018), these findings have two possible interpretations: the altered glucose metabolism either stems from a basic alteration of calcium homeostasis or is the primary defect, linked to the MH syndrome. The high prevalence of hyperglycemia in MHS patients marks the associated changes in calcium signaling and glucose metabolism as diabetes prodromes, appearing decades before disease onset. (£¿p<0.05)
%U https://www.cell.com/biophysj/fulltext/S0006-3495(18)33348-4