One of the major clinical problems of patients with PWS is decreased muscle tone and muscle weakness leading to delayed gross motor milestones and additional clinical problems (e.g. scoliosis) later in life. Interestingly, there is significant lack of knowledge regarding the underlying abnormalities of skeletal Muscle in patients with PWS, nor is there anything known about potential molecules involved in these abnormalities. The current proposal is designed to shed light into abnormalities of skeletal muscle in patients with PWS. In collaboration with Drs. Resnick and Brunelli, we will study mouse models of PWS, which will enable us to characterize skeletal muscle abnormalities on various levels. This will include analyses of potential structural abnormalities and/or changes in size of muscle as well as functional analyses of muscle strength and fatigue. Furthermore, we will test, whether muscle of PWS mice has a normal ability to repair muscle injury. We will attempt to establish a molecular fingerprint of PWS skeletal muscle by analyzing many known pathways critical for normal muscle function and survival. Lastly, we will test specifically, whether necdin, a gene absent in patients with PWS plays a critical role in the skeletal muscle abnormalities of mice with PWS. Together, these studies will help us better understand the nature of skeletal muscle abnormalities in patients with PWS. Furthermore, we hope to be able to identify whether necdin (or potential other proteins) are valuable targets for future therapeutic applications to treat skeletal muscle abnormalities in PWS.
Our preliminary analyses demonstrate that muscles of PWS mouse models have structural changes of skeletal muscle including neuromuscular junctions, which likely explains the severe muscle weakness in young patients with PWS. We have not yet been able to study older mouse models of PWS to see whether these changes improve with age. This will be an important next step. Furthermore, it appears that necdin is indeed a very critical regulator of muscle mass and strength and this warrants further investigation as a therapeutic target.
Ronald Cohn, MD
Johns Hopkins University School of Medicine