Loss of MAGEL2 and hypotonia in Prader-Willi syndrome

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.

Research Outcomes: Project Summary

The aim of this project was to determine whether interventions that alter fuel usage either improve or worsen muscle function and fat accumulation in mice lacking Magel2. Magel2 mice are a genetic model of PWS, and these mice have low activity, weak muscles, and excess fatty tissue. Diazoxide is a potassium channel activator that acts in part by reducing insulin release from the pancreas, and also affects the activity of receptors in the brain. An extended release form of diazoxide, called DCCR, is currently being tested in a randomized clinical trial in children with PWS.  We tested whether diazoxide could alter body weight, muscle mass and fat mass, or metabolism in the Magel2 mouse model. We found that chronic diazoxide treatment decreases fat mass and improves endurance capacity in the Magel2 mouse model of Prader-Willi syndrome. This study demonstrates that the biological pathways impacted by diazoxide may be rational pharmacological targets in PWS and other disorders diseases associated with obesity. 

Research Outcomes: Publications

Chronic diazoxide treatment decreases fat mass and improves endurance capacity in an obese mouse model of Prader-Willi syndrome. Bischof JM, Wevrick R. Molecular Genetics and Metabolism. 2018 Apr;123(4):511-517.

Muscle dysfunction caused by loss of Magel2 in a mouse model of Prader-Willi and Schaaf-Yang syndromes. Kamaludin AA, Smolarchuk C, Bischof JM, Eggert R, Greer JJ, Ren J, Lee JJ, Yokota T, Berry FB, Wevrick R. Human Molecular Genetics. 2016 Sep 1;25(17):3798-3809.

Dopamine pathway imbalance in mice lacking Magel2, a Prader-Willi syndrome candidate gene. Luck C, Vitaterna MH, Wevrick R.  Behavioral Neuroscience. 2016 Aug;130(4):448-59