Grant: Project Grant

More than 50,000 Canadians live with a neuromuscular disease (NMD), and the economic burden for families and the health care system, is significant. NMD progressively reduces skeletal muscle strength, which impacts independence and can shorten lifespan. Despite this, there are no cures for NMDs. Emery-Dreifuss muscular dystrophy (EDMD) is a type of NMD caused by mutations in genes that encode for proteins associated with the nuclear envelope, which is a membrane that encloses the genetic material in every cell of the body, protecting it from damage. Mutations in nuclear envelope proteins can make muscle fibres more susceptible to damage by a normal muscle contraction, and this is thought to cause muscle weakness in EDMD. Nuclear envelope proteins are also found in muscle stem cells, which repair the damaged fibres throughout life in healthy muscle, so EDMD mutations may also affect the ability of muscle stem cells to repair skeletal muscle. However, this is currently unknown. The goal of this research project is to determine if and how EDMD-associated nuclear envelope proteins influence muscle stem cell repair. First (Aim 1), we shall assess when and where each of four EDMD-associated proteins is found in muscle stem cells and their progeny. Next (Aim 2), we will remove these proteins, to study how the loss influences the ability of the stem cells to repair muscle tissue. We will then (Aim 3) identify strategies to restore the ability of muscle stem cells to repair muscle, even when EDMD-associated proteins are disabled. Finally (Aim 4), we will leverage humanized EDMD culture assays to establish pre-clinical evidence that the biology discovered herein is conserved across species. Together, this research will identify if a stem cell defect contributes to EDMD disease progression, and aspires to establish a potential drug treatment strategy to treat patients.