Muscle Stem Cell Fate is Directed by the Mitochondrial Fusion Protein OPA1

FieldValue
dc.contributor.authorBaker, Nicole
dc.date.accessioned2021-04-06T16:01:55Z
dc.date.available2021-04-06T16:01:55Z
dc.date.issued2021-04-06
dc.identifier.urihttp://hdl.handle.net/10393/41974
dc.identifier.urihttp://dx.doi.org/10.20381/ruor-26196
dc.description.abstractDuring aging there is a decline in (MuSCs) and muscle regeneration, though the underlying reason is unknown. Interestingly, mitochondrial fragmentation is a common feature in aging, however, how this impacts MuSC function and maintenance has not been investigated. To address the effect of mitochondrial fragmentation in MuSCs, we generated a knockout mouse model using the Pax7CreERT2 inducible system to target deletion of the mitochondrial fusion protein Opa1 specifically within MuSCs (Opa1-KO). Analysis of MuSC function following muscle injury revealed a defect in the regenerative potential of Opa1-KO MuSCs. Moreover, following injury there was a substantial decrease in the number of MuSC in Opa1-KO animals with a concomitant increase in the number of committing cells, illustrating that loss of Opa1 drives MuSC towards commitment at the expense of self-renewal. Furthermore, loss of Opa1 in MuSCs alters the quiescence state, priming MuSCs for activation, as indicated by a reduction in quiescence-related genes, increased EdU incorporation, and enhanced cell cycle kinetics. To address the impact of mitochondrial dysfunction on muscle stem cell capacity, we generated a model of chronic Opa1 loss. Analysis of muscle stem cell function 3 months after Opa1 ablation revealed mitochondrial dysfunction and a defect in proliferation upon activation, leading to failed muscle regeneration. These data are the first to demonstrate a novel role for mitochondrial structure in the regulation of MuSC maintenance and regenerative capacity.
dc.language.isoen
dc.publisherUniversité d'Ottawa / University of Ottawa
dc.subjectMuscle Stem Cells
dc.subjectMitochondrial Dynamics
dc.subjectStem Cell Fate
dc.subjectOPA1
dc.subjectQuiescence
dc.subjectActivation
dc.subjectMetabolism
dc.subjectGene Expression
dc.subjectMuscle Regeneration
dc.subjectAging
dc.titleMuscle Stem Cell Fate is Directed by the Mitochondrial Fusion Protein OPA1
dc.typeThesis
dc.contributor.supervisorKhacho, Mireille
thesis.degree.nameMSc
thesis.degree.levelMasters
thesis.degree.disciplineMédecine / Medicine
uottawa.departmentBiochimie, microbiologie et immunologie / Biochemistry, Microbiology and Immunology
CollectionThèses, 2011 - // Theses, 2011 -

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