Children with PWS are hypotonic (floppy) at birth. Their poor muscle tone causes delays in sitting and walking and contributes to orthopedic problems such as scoliosis. Reduced endurance lowers the number of calories they can consume per day to manage their body weight, and impairs their quality of life. Treatments that build muscle mass or improve exercise tolerance are key to controlling body weight and preventing scoliosis in PWS.
We are studying mice that are missing one of the genes that is inactivated in children with PWS, called MAGEL2. Children who have mutations in only the MAGEL2 gene also have severe prenatal hypotonia. MAGEL2 is likely the gene that causes muscle problems in PWS. We found that mice missing MAGEL2 have many symptoms that resemble PWS: abnormal endocrine function, infertility, abnormal behavior and increased fat mass. Recently, we found that mice missing MAGEL2 also have low muscle mass, and reduced strength, activity and endurance. We think that this is in part because the muscle cells of mice missing MAGEL2 do not properly use the energy that is supplied by the food that they eat.
We will test whether changing the fat to carbohydrate composition of food given to the mice improves or worsens the function of their muscles. Another group of mice will be fed a nutritional supplement (HMB) that is used by athletes and medically to preserve muscle mass. A final group of mice will be given diazoxide, a drug that is currently in clinical trials in PWS that may be effective in preventing muscle weakness. We will then measure muscle strength, endurance and metabolism in the treated mice.
This study will show how the loss of function of one of the PWS genes, MAGEL2, causes muscle weakness throughout life in PWS. We will focus on dietary interventions and treatment with readily available compounds. This way, positive results in the mice can be readily translated into clinical trials that evaluate the management of muscle tone and endurance in children with PWS. This study will also set the stage for future studies in mice using drugs already in development for the treatment of other forms of muscle weakness.
This project was funded by the Foundation for Prader-Willi Research Canada.