Graduate Student University of Southern California (USC), California, United States
Abstract: Duchenne muscular dystrophy (DMD) is a currently incurable muscle-wasting disease that typically leaves children wheelchair bound by 10 and usually dead by their 20s. DMD is caused by the loss of Dystrophin, a structural protein that maintains skeletal muscle integrity. Although Dystrophin is lost at birth, severe muscle loss does not occur until later in adolescence, coinciding with the decline in muscle stem cell (MuSC) function. Human DMD patient progression and DMD mouse model data suggests that preserving muscle-forming ability through MuSCs is key to preserving muscle mass in DMD patients. This raises two unresolved questions: (1) what are the molecular driver(s) of MuSC dysfunction in DMD; and (2) how can therapies be developed to reverse MuSC dysfunction, prevent muscle loss, and prolong DMD patient lives? Our laboratory recently identified a stress-response pathway, FOS, which is transiently expressed in healthy adult MuSCs and is necessary for stem cell activation and regeneration of skeletal muscles. However, when FOS was continuously expressed in muscle progenitor cells, these cells failed to differentiate into muscle ex vivo and we identified a gene expression profile consistent with loss of stem cell differentiation, identity, and muscle fiber stability, phenotypes that resemble the pathology of DMD. In essence, we recreated a DMD-like phenotype ex vivo by shifting FOS from transient to continuous expression. Consistent with this model, our preliminary data shows that FOS is continuously expressed in 30-40% of DMD MuSCs before and after injury in vivo when compared to healthy MuSCs in a D2.mdx mouse model, suggesting that FOS is chronically activated in a subset of DMD MuSCs. Based on our findings, I will test the hypothesis that chronic FOS activation is a driver of MuSC dysfunction and leads to muscle wasting and weakness in DMD mice; and that restoring proper FOS activation in DMD MuSCs can reverse stem cell dysfunction and DMD muscle pathology. By targeting FOS, our work aims to clarify its role in DMD pathology and identify FOS as a therapeutic target, with the potential to improve muscle function and extend patient lifespans.
Funding Source: California Institute for Regenerative Medicine (CIRM) EDUC4 Fellowship
