Role of STAT3 signaling in muscle stem cell activation

Sanford Burnham Prebys Medical Discovery Institute, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): Adult muscle stem cells (MuSC), also known as satellite cells, are the main source skeletal muscle regeneration. This is due to their ability to self-renew in vivo, i.e. to generate upon cell division more copies of themselves as well as give rise to committed progeny, as we have conclusively demonstrated by single MuSC transplantation. MuSC exist in healthy adult tissues in a quiescent state, and upon stress or injury they are activated to proliferate and generate large numbers of progenitors to repair the damaged tissue. Although the balance between quiescence and activation is a critical switch in MuSC function, the molecular mechanisms regulating this transition are still largely unknown. A more clear understanding of the regulatory networks underlying MuSC activation might provide novel targets that would aid in the development of therapeutic approaches to ameliorate muscle-wasting diseases. Our preliminary findings indicate for the first time that STAT3 plays a direct role in the transcriptional activation of the bHLH myogenic regulatory factor MyoD, a key event as MuSC exit the quiescent state. STAT3 is a transcription factor that plays a major role in self-renewal of several types of stem cells, including embryonic, intestinal and hematopoietic compartments. Upon cytokine stimulation, STAT3 is phosphorylated by JAK kinases, it homodimerizes, translocates to the nucleus and binds DNA to activate the transcription of target genes. Although it has been previously shown that STAT3 is activated upon skeletal muscle injury, its role in MuSC activation as well as its relevant downstream targets are still poorly understood. Accordingly, the focus of this proposal is to investigate the role of the JAK/STAT3 pathway in MuSC activation and its functional interaction with MyoD. Our research will take advantage of the following tools: (1) Loss of function studies in conjunction with time-lapse microscopy, to monitor MuSC activation, proliferation and survival in vitro, (2) Luciferase reporter assay using deletion mutants of the MyoD proximal enhancer, to validate the direct role of STAT3 in MyoD transcriptional activation, (3) Conditional genetic ablation of STAT3 in MuSC, in order to evaluate its role in MuSC function in vivo in the intact animal. Together, these studie would constitute a conceptual advancement in the field, as they would identify a direct functional interaction between JAK/STAT3 and MyoD, and further extend our knowledge of the regulatory network in MuSC activation. Finally, these findings would aid in the development of strategies aimed at promoting muscle stem cell-mediated tissue regeneration to ameliorate muscle-wasting diseases.