Altered calcium handling in Central Core Disease and Malignant Hyperthermia: understand molecular mechanisms and genetic background to develop innovative therapeutic interventions

The goal of this project is to lay the groundwork for the development of pharmacological treatments for two myopathies: central core disease (CCD) and malignant hyperthermia susceptibility (MHS). CCD and MHS are related syndromes because i) many patients with CCD test positive for MHS and ii) many cases in both, even if not all, are linked to mutations in RYR1, the Ca2+ release channel of muscle. CCD, one of the most common human congenital myopathies, is characterized by muscle weakness (severe in some cases) and causes significant motor developmental delay in children. The histological analysis of muscle biopsies reveals the presence of areas, or cores, lacking mitochondria, the organelles providing energy. MHS is a clinical syndrome in which genetically predisposed individuals respond to administration of volatile anesthetics with life-threatening elevations in body temperature. In our views, though, MH can be also triggered by heat or physical exertion. Whereas an effective treatment is available for anesthetic MH (dantrolene), no curative treatments are yet available for management of CCD patients and for MH-related syndromes. We will: 1) investigate the mechanisms leading to mitochondrial loss in cores, studying the disease in human biopsies and in several different animal models; 2) demonstrate that MH episodes triggered by heat and exertion share common mechanisms and genetics with anesthetic-MH; 3) attempt to identify novel genes/mutations responsible for CCD, and for anesthetic- and non-anesthetic MH; 4) couple these advancements to the development of interventions capable of preventing/reducing cores formation in CCD and treat MH episodes caused by heat and exertion. In this regard, in this project we will test several new drugs capable of controlling abnormal Ca2+ handling, responsible of muscle dysfunction.