In partial fulfillment of the requirements for the degree of

Doctor of Philosophy in Biology

In the

School of Biological Sciences

Jeong Moon Choi

Will defend her dissertation

Understanding Intrinsic and Extrinsic Regulations of Aged Muscle Stem Cells

Thursday, December 2nd, 2021

2PM

https://bluejeans.com/458102278/9851

 Thesis Advisor:

Young Jang, Ph.D.

School of Biological Sciences

Georgia Institute of Technology

Committee Members:

Matthew Torres, Ph.D.

School of Biological Sciences

Georgia Institute of Technology

Yuhong Fan, Ph.D.

School of Biological Sciences

Georgia Institute of Technology

Shuichi Takayama, Ph.D.

School of Biomedical Engineering

Georgia Institute of Technology

& Emory University

Holly Van Remmen, Ph. D.

Aging & Metabolism Research Program

Oklahoma Medical Research Foundation

ABSTRACT

Skeletal muscle plays a vital role in extending health-span, a disease-free state during chronological aging. Skeletal muscle homeostasis is maintained by dedicated tissue stem cells called muscle satellite/stem cells (MuSC), which undergo asymmetric divisions of self-renewal to maintain their pool size or proliferation-differentiation to fuse into existing multinucleated muscle fibers to regenerate an injured muscle. It has been well documented that age-associated muscle loss and function are caused by decreased bioavailability of MuSCs. While many studies focused on factors altering MuSC function as we age, we still do not fully understand age-acquired deficits in MuSCs in the late stages of life. Thus, therapeutic interventions targeting MuSCs to restore the functionality of aged skeletal muscle have not been developed. The overarching goal of my thesis is to understand how MuSCs drive sarcopenia and frailty. We hypothesized that age-related internal and external changes in muscle stem cell are one of the main drivers of skeletal muscle aging and frailty. To test our hypothesis, the first project focused on the intrinsic changes of MuSCs, specifically, the consequences of mitochondrial dysfunction on aged myofibers. Based on the results, we developed a transplantation strategy to restore the mitochondrial network and function in the host aged muscle by fusing young healthy MuSC-derived mitochondria. The second project examined how extrinsic factors of the MuSC microenvironment influence MuSC function, particularly a cell-cell communication between MuSCs and motor neuron through a neuromuscular synapse. We found that transient disruption of innervation revitalized MuSC function by enhancing bioenergetics and protein synthesis. On the other hand, persistent loss of nerve supply, common phenotypes in the aged muscle, altered MuSC-motor neuron communication, which had no effect on myogenic function. In the third project, we studied how the change of systemic humoral factors alters MuSC myogenesis in the aged. We assessed whether the young systemic milieu restores the aged MuSC function using a 3D engineered heterochronic parabiosis system.

All in all, we leveraged in vitro and in vivo stem cell engineering approaches to gain insights on intrinsic and extrinsic changes that occur during aging and how they impair muscle stem cell function during aging. Our data imply that MuSC function is compromised by mitochondrial dysfunction, interruption of intercellular communication, and aberrant systemic factors in aged muscle. Furthermore, we demonstrated that heterochronic transplantations of young healthy MuSCs or by modifying the circulating factors to those found in a young muscle environment, aged MuSCs and muscle can be rejuvenated. This work sheds light on previously unknown intrinsic and extrinsic factors impacting MuSC function and provides a viable target for therapeutic interventions to restore the regenerative capacity of aged muscle.