Abnormal sarcoplasmic reticulum ryanodine receptor in malignant hyperthermia

Area of Science:

• Physiology
• Molecular Biology
• Pharmacology

Background:

• Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle.
• Individuals susceptible to MH exhibit defects in intracellular calcium release from the sarcoplasmic reticulum (SR).

Purpose of the Study:

• To investigate the properties of the ryanodine receptor (RyR) in MH-susceptible (MHS) porcine skeletal muscle.
• To determine if alterations in the RyR contribute to the abnormal calcium handling in MHS muscle.

Main Methods:

• Isolated MHS and normal porcine heavy SR were used for [3H]ryanodine binding assays.
• Ryanodine binding affinity (Kd) and capacity (Bmax) were analyzed.
• SR proteins were analyzed by SDS-PAGE.
• Intact MHS and normal porcine muscle fiber bundles were studied for ryanodine effects on contracture and inhibition.

Main Results:

• MHS porcine SR exhibited altered Ca2+ dependence of [3H]ryanodine binding at the low affinity Ca2+ site.
• MHS porcine SR showed a lower Kd for ryanodine (92 vs. 265 nM) compared to normal SR.
• No significant difference in Bmax or SR protein staining was observed between MHS and normal SR.
• MHS muscle fiber bundles displayed a 5-10 fold lower ryanodine threshold for twitch/tetanus inhibition and contracture onset.

Conclusions:

• Abnormalities in the skeletal muscle ryanodine receptor may underlie the defective SR calcium release in MHS muscle.
• The SR ryanodine receptor, a calcium release channel, is implicated in transverse tubule-SR communication.
• Altered RyR function in MHS muscle contributes to abnormal muscle contractile properties.