MDA awarded a grant totaling $375,000 to Francesco Muntoni, professor of pediatric neurology at University College London (UCL), United Kingdom, for research into the molecular mechanisms underlying central core disease (CCD) and multiminicore myopathies. Muntoni and Michael Duchen, professor of physiology, and cell and developmental biology, also at UCL, will work together, focusing on the mechanisms that lead to muscle weakness in the two diseases.

CCD and multiminicore myopathies both are caused by mutations in the ryanodine receptor gene (RYR1), which carries instructions for the RYR1 protein.

"While we have known for a number of years that RYR1 gene mutations were associated with these core myopathies, the precise mechanism leading to muscle weakness in affected individuals is less clear," Muntoni said.

It's known that RYR1 plays a key role in the release of calcium in skeletal muscle; the calcium release is followed by muscle contraction.

Muntoni and Duchen will investigate the hypothesis that chronic calcium dysregulation due to dysfunctional RYR1 protein leads to malfunction, in each muscle fiber, of the cell's energy factories, called mitochondria. With muscle cells from individuals carrying RYR1 mutations, the two will study various aspects of mitochondria health and function following exposure to abnormal calcium release.

"This study is a follow-on of a currently funded MDA grant that is coming to an end," Muntoni said. "The current MDA grant allowed us to improve our insight on the correlation between different mutations in RYR1 and the core myopathies. Without the original MDA grant, we would not have been in a position to establish these novel correlations between RYR1 and congenital diseases."

An improved understanding of the link between dysregulated calcium handling and mitochondria dysfunction could lead to new therapeutic interventions for individuals with core myopathies.

Funding for this MDA grant began August 1, 2010.