The Role of Twist2 in Physiologic and Pathologic Myogenesis

Date

2019-05-01

Authors

Li, Stephen

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Abstract

Skeletal muscle is a highly regenerative tissue required for vertebrate life. It composes a significant portion of body mass and enables the physiologic processes of movement and breathing. Given its importance, skeletal muscle is also highly susceptible to aging and diseases such as cancer. Aging-related muscle atrophy (sarcopenia) is a process that affects nearly every person, contributing to debilitations and reductions in quality of life. As people age, fast-twitch muscle fibers selectively atrophy resulting in weakness. Normally, muscle regenerates through a population of stem cells called satellite cells, which differentiate and non-selectively fuse to existing myofibers in order to repair the damaged muscle tissue. However, several recent studies have suggested that the contribution of satellite cells to muscle during homeostasis and aging is minimal. Thus, it's possible that loss of an alternative muscle precursor that fuses specifically with fast-twitch fibers may be a mechanism by which aging-related muscle atrophy occurs. Through the technique of lineage-tracing (fate-mapping) of the transcription factor Twist2, we have identified a novel muscle progenitor that fuses specifically to type IIb/x (fast-twitch, glycolytic) muscle fibers during both aging and homeostasis. Additionally, loss of Twist2+ cells result in specific atrophy of fast-twitch myofibers. I show that Twist2 plays a role in regulating fiber-type specificity through upregulation of the membrane receptor Nrp1. Additionally, the Nrp1 chemo-repulsive ligand, Sema3a, is expressed by both type I and IIa fibers. This Sema3a-Nrp1 signaling mechanisms prevents Twist2+ cells from fusing to type I and IIa fibers, and exogenous overexpression of Sema3a in type IIb fibers impairs the contribution of Twist2+ cells to these fibers. I also found that Twist2 is highly amplified in rhabdomyosarcoma (RMS), a pediatric soft tissue sarcoma expressing hallmarks of the skeletal muscle lineage. Twist2 overexpression was capable of reversibly repressing myogenesis and promoting dedifferentiation of myotubes. Through integrated genomic analyses, I show that Twist2 epigenetically remodels the chromatin landscape to redirect MyoD binding from myogenic loci to oncogenic loci, enabling MyoD to adopt novel functions. Our findings identify the previously unknown roles of Twist2 in regulating mammalian muscle biology.

General Notes

The file named "LI-DISSERTATION-2019.pdf" is the primary dissertation file. Two (2) supplemental video files are also available and may be viewed individually.

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