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J.Petrosino_Diss_11.16.21.pdf (58.83 MB)

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Size Matters: Molecular Mediators of Muscle Mass

Petrosino, Jennifer Morgan
http://rave.ohiolink.edu/etdc/view?acc_num=osu163758903844252

Abstract Details

2021, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
Skeletal muscle is highly adaptable, and in response to anabolic stimuli, neuronal innervation, and mechanical overload, undergoes an increase in myofiber cross-sectional area called hypertrophy. Hypertrophy requires global increases in protein synthesis, which ultimately drive increases in muscle cell size and mass. The majority of discovered mechanisms known to regulate muscle cell size focus on epigenetic DNA and post-translational protein modifications; however, the necessity of gene expression regulation for muscle growth is unknown. Here we identify three different novel proteins involved in overload-induced gene expression regulation that are essential for muscle hypertrophy. Through a combination of genetic mouse models and hypertrophy-induing synergist ablation assays, three overload-responsive genes were identified. We found that each identified gene is essential for muscle growth. In the first chapter, we detail our finding of how myofiber-derived Cell Communication Network Factor 2 (CCN2) is required for muscle growth and how it functions to regulate focal adhesion kinase-mediated transduction of overload-induced extracellular signals and their regulatory impact on hypertrophic muscle protein synthesis. In the second chapter of this work, we demonstrate how in muscle, the mRNA modifying enzyme Methyltransferase Like 3 (METTL3), functions to regulate anabolic muscle growth by ii providing an inhibitory methylation mark on the pro-atrophic Activin Receptor mRNA and thus acts to post-transcriptionally regulate the myostatin pathway and muscle cell size. In the third chapter of this dissertation, we reveal the role of injury and overload-induced Brain-Expressed-X-Linked 1 (BEX1), which is necessary for reparative growth and the translation of postsynaptic Arc, a key regulator of muscle’s adaptive neuromuscular plasticity. While the main contributions of this work are the identification of novel molecular mediators of muscle mass and the preclinical demonstration that they can be used therapeutically to enhance muscle mass, there is also a significant contribution from this work involving its ability to shed light on the black box that is post-transcriptional regulation of muscle growth.
Federica Accornero (Advisor)
Juan Alfonzo (Committee Member)
Denis Guttridge (Committee Member)
Scott Harper (Committee Member)
Jill Rafael-Fortney (Committee Member)
120 p.
Biochemistry; Biology; Biomedical Research; Medicine; Molecular Biology; Physiology
skeletal muscle; transcription; mRNA modification; growth; hypertrophy; mechanosiganling; RNA; translational control; regeneration; gene expression

Recommended Citations

Citations

  • Petrosino, J. M. (2021). Size Matters: Molecular Mediators of Muscle Mass [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu163758903844252

    APA Style (7th edition)

  • Petrosino, Jennifer. Size Matters: Molecular Mediators of Muscle Mass. 2021. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu163758903844252.

    MLA Style (8th edition)

  • Petrosino, Jennifer. "Size Matters: Molecular Mediators of Muscle Mass." Doctoral dissertation, Ohio State University, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=osu163758903844252

    Chicago Manual of Style (17th edition)

osu163758903844252
74
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This open access ETD is published by The Ohio State University and OhioLINK.
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