Project 6 - Myostatin in normal and diseased muscle

Principal investigator
Simone Spuler, MD, Prof 

Our group is studying myostatin. Myostatin (also known as growth differentiation factor 8) is a secreted TGF-ß protein family member that inhibits muscle differentiation and growth. During the first funding period, we delineated the role of myostatin in muscular dystrophies associated with mutations in dysferlin (LGMD2B/MM), a large sarcolemmal protein involved in membrane repair. We found that myostatin severely inhibits human myotube differentiation and increases the expression of fibrosis-associated proteins. These results are in accordance with the literature and extend the findings, as the myostatin-related effects on dysferlin-deficient muscle are far more pronounced than on normal controls. We also found that myostatin induces certain splice variants of calpain 3 (CAPN3), a muscle specific protease located in the sarcolemma in close association with titin. CAPN3 is thought to regulate access of the ubiquitine-proteasome system to the sarcolemma and may play a key role in sarcolemmal protein turnover. Finally, we have a new approach to study the effects of myostatin in models of dysferlin deficiency. We will focus our present proposal on elucidating the molecular mechanisms of CAPN3 activity under myostatin influence. We continue our intensive interest in dysferlin. This project targets the CRG's mission and benefits from the unique expertise of many CRG project leaders.