Title:
Muscle Stem Cells Regulate the Bioenergetic Function of Myofibers in Mitochondrial Myopathies
Muscle Stem Cells Regulate the Bioenergetic Function of Myofibers in Mitochondrial Myopathies
Author(s)
Mohiuddin, Mahir
Advisor(s)
Jang, Young C.
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Abstract
Skeletal muscle tissue exhibits a high degree of plasticity due to their muscle stem cells, which are indispensable for muscle fiber repair, and the unique architecture of their mitochondria, which provide the energy for muscle fiber function, maintenance, and regeneration. In response to injury, quiescent muscle stem cells (MuSCs) undergo myogenesis to activate, differentiate, and fuse into the muscle fiber as new myonuclei that regulate myofiber repair. To meet the high energy demands of muscle regeneration, MuSCs increase in mitochondrial content through the various phases of myogenesis. However, when muscle mitochondria become dysfunctional, such as in peripheral artery disease (PAD) and Duchenne muscular dystrophy (DMD), MuSCs are debilitated and myofiber mitochondria remain defective, resulting in mitochondrial myopathy. Despite the characterization of mitochondrial dysfunction in these two disease models, the relationship between MuSC mitochondria and the bioenergetic function of the myofiber has not been investigated. To address this, the overarching objective of this thesis was to explore the role of MuSCs in remodeling the mitochondrial network and function of the myofiber in mitochondrial myopathies. We first correlated the MuSC response with the stages of mitochondrial network remodeling following a murine hindlimb ischemia (HLI) model of PAD and discovered that MuSC-derived myonuclei drive mitochondrial biogenesis. As direct evidence of MuSC-mediated remodeling of mitochondria, we then revealed that mitochondrial dysfunction in the MuSC yields deficient bioenergetic function of the dystrophic myofiber, which can be rescued by transplantation of MuSCs with healthy mitochondria. We tested this further in ischemic muscle after aging, which exacerbated the mitochondrial dysfunction, and again observed significant improvements in bioenergetic function following transplantation of healthy MuSCs. Overall, this thesis established that MuSC mitochondria play a consequential role on myofiber bioenergetic function, identified a source of mitochondrial dysfunction in dystrophic muscle, developed a model of age-associated PAD, and provided a conceptual framework for MuSC transplantation as a therapeutic approach for mitochondrial myopathies.
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Date Issued
2021-07-14
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Text
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Dissertation