Oral Presentation 2014 International Biophysics Congress

The puzzling phenotype of calsequestrin-1 knockout mice: What have we learned? (#42)

Feliciano Protasi 1
  1. CeSI - Centre for Research on Aging, University G. d'Annunzio, Chieti, Italy

Calsequestrin type 1 (CASQ1), the main sarcoplasmic reticulum (SR) Ca2+ binding protein, plays a dual role in skeletal muscle fibers: a) it provides a large pool of rapidly-releasable Ca2+ during excitation-contraction (EC) coupling; and b) it modulates the activity of ryanodine receptors (RYRs), the SR Ca2+ release channel.  A few years ago, we generated a mouse lacking CASQ1 (CASQ1-null): contrary to initial expectations, we soon realized that CASQ1-null mice were viable, and that ablation of CASQ1 was compatible with normal motor activity, in spite of moderate muscle atrophy.  However, CASQ1 deficiency resulted in profound structural remodeling of the EC coupling apparatus and significant functional impairment: prolonged time course of contraction, reduced size of Ca2+ transients, increased rate SR Ca2+ depletion, and inability to sustain tension during a prolonged tetani. Though, we were soon faced with the puzzling observation of an increased spontaneous mortality of mice in the colony and discovered that mice lacking CASQ1 exhibited lethal hyperthermic episodes when exposed to either halothane or heat. The presentation of those episodes was quite similar to that of a) malignant hyperthermia (MH), in which hyperthermic episodes triggered by volatile anesthetics are linked to mutations in the skeletal muscle Ca2+ release channel (RYR1), and of b) environmental heat stroke (EHS), a life-threatening condition triggered by hot temperatures. In recent, still unpublished, experiments we are investigating if the halothane- and heat-induced episodes results from common molecular mechanisms.  These studies indicates that a) MH-like and EHS lethal crises can both be prevented by the drug used in the operating room to treat acutely MH crises (dantrolene), suggesting a similar pathophysiology; and b) oxidative stress plays a key role during over-heating crises, as a potent anti-oxidant (N-acetylcysteine) is quite effective in protecting mice from sudden death.