Blocking Myofiber Necrosis in Treating Dysferlinopathy by Ameliorating Calcium Dysregulation

Jeffery Molkentin, PhD

Children’s Hospital, University of Cincinnati (Cincinnati, OH)

Dr. Molkentin is a Professor in the Department of Pediatrics at the Children’s Hospital Medical Center, of the University of Cincinnati (Cincinnati, OH).

Past Projects

Objective: 
Investigate approaches to rescuing the disease phenotype by minimizing calcium dysregulation

Many types of muscular dystrophy are associated with either membrane instability (for instance, Duchenne muscular dystrophy) or impaired membrane repair following damage (dysferlin deficiency). Damage to the cell membrane causes an influx of calcium ions, which can lead to cell death. To better understand the manner in which calcium influx and an unstable sarcolemma might lead to myofiber necrosis and MD we have undertaken a number of transgenic approaches in mice with altered calcium influx or removal. For example, in the past year we published a paper showing that transient receptor potential canonical (TRPC) regulated aspects of calcium influx that causes MD. TRPC channels are known calcium and sodium influx channels that are activated in dystrophic muscle due to an unstable membrane. TRPC channels are an attractive candidate target for therapeutic intervention in many muscular dystrophies (including dysferlinopathy) because pharmacologic inhibitors are in late stage development. We are investigating the role of altered calcium regulation by crossing animal models with altered calcium handling with dystrophic models.