Influence of Notch Inhibition on Mtor and Wnt Signaling in Reparing Muscle

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Williams III, J. (2023). Influence of Notch Inhibition on Mtor and Wnt Signaling in Reparing Muscle. Unc Charlotte Electronic Theses And Dissertations.
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Abstract

Protein synthesis and muscle stem cells are crucial components of adequate muscle repair in healthy individuals that are dysregulated in a variety of diseases states. A key regulator of muscle stem cell activation and coordination of downstream muscle repair is the evolutionary conserved Notch signaling pathway. Notch signaling is instrumental in cell fate determination during embryonic myogenesis and mature tissue repair. Furthermore, the mechanistic target of rapamycin (mTOR) and Wingless/Integrated (Wnt) are closely linked to Notch signaling in a variety of other tissues and their interactions are widely studied. However, the exact mechanisms by which they coregulate in skeletal muscle is not fully understood. The convergence of these three signaling networks in skeletal muscle is an area which demands further exploration so effective therapies for the growing global obese and aged population may be developed. Our lab has previously measured the effect Notch1 shRNA knockdown had on muscle protein synthesis (MPS) and found Notch inhibition significantly increased mTOR signaling and MPS. Our attempt to elucidate the interaction of Notch, mTOR, and Wnt utilized Notch1 shRNA lentiviral knockdown and an injurious bout of downhill running. We investigated the effect of these interventions on key downstream regulators of mTOR and Wnt to understand the mechanisms by which Notch1 knockdown increases muscle protein synthesis. We observed no significant differences between empty vector and Notch1 inhibited limbs in P70S6K or 4EBP1, indicating Notch1 shRNA inhibition and DHR was not sufficient to induce changes. However, there were significant time-course changes in GSK3 expression, suggesting a relationship between Notch and Wnt signaling via GSK3. These findings contribute to the growing understanding of the synergistic roles played by Notch, mTOR, and Wnt signaling in the muscle repair process.

Details
Author

Williams III, James

Title

Influence of Notch Inhibition on Mtor and Wnt Signaling in Reparing Muscle

Physical Description

1 online resource ( pages) : PDF

Date

2023

Degree Granting Institution

University of North Carolina at Charlotte

Abstract

Protein synthesis and muscle stem cells are crucial components of adequate muscle repair in healthy individuals that are dysregulated in a variety of diseases states. A key regulator of muscle stem cell activation and coordination of downstream muscle repair is the evolutionary conserved Notch signaling pathway. Notch signaling is instrumental in cell fate determination during embryonic myogenesis and mature tissue repair. Furthermore, the mechanistic target of rapamycin (mTOR) and Wingless/Integrated (Wnt) are closely linked to Notch signaling in a variety of other tissues and their interactions are widely studied. However, the exact mechanisms by which they coregulate in skeletal muscle is not fully understood. The convergence of these three signaling networks in skeletal muscle is an area which demands further exploration so effective therapies for the growing global obese and aged population may be developed. Our lab has previously measured the effect Notch1 shRNA knockdown had on muscle protein synthesis (MPS) and found Notch inhibition significantly increased mTOR signaling and MPS. Our attempt to elucidate the interaction of Notch, mTOR, and Wnt utilized Notch1 shRNA lentiviral knockdown and an injurious bout of downhill running. We investigated the effect of these interventions on key downstream regulators of mTOR and Wnt to understand the mechanisms by which Notch1 knockdown increases muscle protein synthesis. We observed no significant differences between empty vector and Notch1 inhibited limbs in P70S6K or 4EBP1, indicating Notch1 shRNA inhibition and DHR was not sufficient to induce changes. However, there were significant time-course changes in GSK3 expression, suggesting a relationship between Notch and Wnt signaling via GSK3. These findings contribute to the growing understanding of the synergistic roles played by Notch, mTOR, and Wnt signaling in the muscle repair process.

Genre

masters theses

Subjects--Topics

Kinesiology

Degree

M.S.

Keywords

Mtor
Notch
Skeletal Muscle
Wnt

Subject Area

Kinesiology

Advisor(s)

Arthur, Susan

Committee Members

Marino, Joseph
Huot, Joshue

Degree Note

Thesis (M.S.)--University of North Carolina at Charlotte, 2023.

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Rights Holder Information

Copyright is held by the author unless otherwise indicated.

Identifier

WilliamsIII_uncc_0694N_13499

Permalink

http://hdl.handle.net/20.500.13093/etd:3207