Regulation of Skeletal Muscle Mitochondrial, Quality Control by the Transcription Factors P53 and ATF4

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dc.contributor.advisorHood, David A.
dc.contributor.authorMemme, Jonathan Matthew
dc.date.accessioned2023-03-28T21:16:56Z
dc.date.available2023-03-28T21:16:56Z
dc.date.copyright2022-11-29
dc.date.issued2023-03-28
dc.date.updated2023-03-28T21:16:55Z
dc.degree.disciplineKinesiology & Health Science
dc.degree.levelDoctoral
dc.degree.namePhD - Doctor of Philosophy
dc.description.abstractWell-appreciated for its role in locomotion and posture, the metabolic profile of muscle has extended implications for mobility, along with the onset of disease. It is well-documented that endurance exercise promotes enhanced aerobic capacity, while prolonged disuse results in a diminished respiratory function, accompanied by fiber atrophy and weakness. A unique, and natural, feature of aging is the progressive loss of muscle mass, which develops from molecular changes within muscle that include diminished aerobic capacity and muscle strength. Thus, understanding the molecular mechanisms that promote muscle health or contribute to muscle decline are of considerable importance to identify therapeutic strategies that can preserve muscle function. Mitochondria are the culpable organelles in the maintenance of skeletal muscle metabolic health, and are therefore important regulators of a variety of factors contributing to muscle dysfunction, such as oxidative stress and antioxidants, apoptosis, inflammation, and Ca2+ handling, in addition to their role as the energy hubs of the cell. Mitochondrial quality control (MQC) involves multiple processes that coordinately regulate organellar biogenesis, turnover, and proteostasis (mitochondrial unfolded protein response) to maintain an optimal mitochondrial pool. While recent research has elucidated the importance of this synchronized control, science has yet characterized a single regulator of broad MQC pathways. The transcription factors p53 and ATF4 are two candidates that, in muscle, respond to various stressors, and are positioned at the nexus of these processes. Therefore, we explored the necessity of p53 and ATF4 in mediating mitochondrial adaptations. p53 muscle-specific knockout mice (mKO) had dysregulated signaling for MQC following 1-day of denervation- induced disuse, with further decrements in organelle function and MQC regulation after 7 days, especially with respect to the autophagy-lysosome system. Additionally, through ATF4 overexpression (OE) and knockdown (KD) in C2C12 myotubes, we found ATF4 to be an import mediator of MQC pathways, contributing to an enhanced mitochondrial network with augmented function, following C2C12 myotube differentiation, as well as acute and chronic contractile activity. Our data identify both p53 and ATF4 as two transcriptional regulators that each exhibit multifaceted control of mitochondrial health in muscle during both the pro- and mal-adaptive stimuli of exercise and disuse.
dc.identifier.urihttp://hdl.handle.net/10315/40989
dc.languageen
dc.rightsAuthor owns copyright, except where explicitly noted. Please contact the author directly with licensing requests.
dc.subjectPhysiology
dc.subjectMolecular biology
dc.subjectHealth sciences
dc.subject.keywordsSkeletal Muscle
dc.subject.keywordsMitochondria
dc.subject.keywordsExercise
dc.subject.keywordsMuscle disuse atrophy
dc.subject.keywordsUnfolded protein response
dc.subject.keywordsAutophagy
dc.subject.keywordsMitophagy
dc.subject.keywordsMitochondrial biogenesis
dc.subject.keywordsLysosomal biogenesis
dc.subject.keywordsTFE3
dc.subject.keywordsTFEB
dc.subject.keywordsPGC-1alpha
dc.subject.keywordsC2C12
dc.titleRegulation of Skeletal Muscle Mitochondrial, Quality Control by the Transcription Factors P53 and ATF4
dc.typeElectronic Thesis or Dissertation

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