Aging-related muscle atrophy (sarcopenia) is a process that affects nearly every person, contributing to debilitations and reductions in quality of life. As people grow older, fast-twitch muscle fibers are selectively atrophied 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 to 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 conditions. Additionally, loss of Twist2+ cells result in specific atrophy of fast-twitch myofibers. I hypothesize that Twist2 is playing a role in regulating both the fiber type specificity as well as the quiescence of this novel progenitor cell. To test this hypothesis, we propose to study the genes Neuropilin1 and Suv39h1 through mouse models, stripe migration assays, fusion assay, Chip-Seq, and cell culture studies.

Public Health Relevance

Skeletal muscle is a vital organ and its loss during aging contributes to enormous morbidity. Although it is known that aging results in selective atrophy of fast-twitch muscle fibers, it is not well understood why this occurs. This proposal seeks to study the mechanisms of how Twist2+ cells, a newly identified fast-fiber specific muscle progenitor, regulate their fiber-type specificity and quiescence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30AG056075-03
Application #
9643989
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Williams, John
Project Start
2017-04-01
Project End
2021-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Liu, Ning; Garry, Glynnis A; Li, Stephen et al. (2017) A Twist2-dependent progenitor cell contributes to adult skeletal muscle. Nat Cell Biol 19:202-213