The role of Nix in calcium signaling, gene expression, and oxidative phenotype of skeletal muscle
| dc.contributor.author | Field, Jared | |
| dc.contributor.examiningcommittee | West, Adrian (Physiology and Pathophysiology) | |
| dc.contributor.examiningcommittee | Czubryt, Michael (Physiology and Pathophysiology) | |
| dc.contributor.examiningcommittee | Marzban, Hassan (Human Anatomy and Cell Sciences) | |
| dc.contributor.examiningcommittee | Perry, Christopher (York University) | |
| dc.contributor.supervisor | Gordon, Joseph | |
| dc.date.accessioned | 2024-06-19T19:44:27Z | |
| dc.date.available | 2024-06-19T19:44:27Z | |
| dc.date.issued | 2024-06-11 | |
| dc.date.submitted | 2024-06-11T17:30:33Z | en_US |
| dc.date.submitted | 2024-06-19T15:39:54Z | en_US |
| dc.degree.discipline | Human Anatomy and Cell Science | |
| dc.degree.level | Doctor of Philosophy (Ph.D.) | |
| dc.description.abstract | Mitochondrial quality control is an essential component of muscle biology, with multiple muscular diseases/pathologies associated with dysregulation of this process (e.g., sarcopenia, cachexia, mitochondrial myopathies, and the remodeling associated with obesity and insulin resistance). The protein Nix serves an important role as a mitophagy receptor protein that mediates removal of dysfunctional fragments of mitochondria through the autophagic process. Human genome-wide association studies have connected polymorphisms in the Nix gene with development of mitochondrially-dependent disorders such as schizophrenia and cognitive decline. In muscle, Nix expression has been connected with aging and has been implicated in starvation-induced muscle atrophy. Additionally, Nix has also been implicated as an important factor in models of lipid-induced insulin resistance of muscle, as well as a potential mediator of calcium signaling within the cell. Together this demonstrates the complex, but important, biology of Nix. However, a model to study Nix in skeletal muscle is lacking. To advance our understanding of Nix in physiologically healthy muscle, we generated and characterised a mouse line harbouring a muscle-specific deletion of Nix. I found evidence of compensated mitochondrial myopathy within muscle that manifests as reduced metabolic rate and capacity for aerobic exercise. Intriguingly, I found that Nix also regulates calcium signaling within muscle to produce a shift towards expression fast fiber types when Nix is deleted in muscle. Previously in cell culture experiments, pharmacological inhibition of Nix was found to restore insulin sensitivity following lipotoxicity-induced insulin resistance. With muscle knockout of Nix, I found heightened sensitivity to insulin that was associated with an mTOR/S6K mechanism described previously in cells. Given the variety of roles described for Nix in muscle, I took the first steps towards uncovering muscle-specific regulation of Nix expression through in vitro studies. To this end, I found that Nix is a direct target of the transcription factors MEF2D of the myogenic program. In summary, I found that deletion of Nix has multiple possible protective effects including protecting metabolism from lipid overload while also directing muscle oxidative phenotype. I have characterized a model to study the biology of Nix, which in addition to novel findings related to calcium and myostatin signaling, provides the basis to study Nix in diseases of muscle or diseases that etiologically involve muscle. | |
| dc.description.note | October 2024 | |
| dc.identifier.uri | http://hdl.handle.net/1993/38260 | |
| dc.language.iso | eng | |
| dc.rights | open access | en_US |
| dc.subject | Nix | |
| dc.subject | Skeletal muscle | |
| dc.subject | Calcium signaling | |
| dc.subject | Muscle fiber type | |
| dc.subject | Mitochondrial myopathy | |
| dc.subject | Mitophagy | |
| dc.title | The role of Nix in calcium signaling, gene expression, and oxidative phenotype of skeletal muscle | |
| dc.type | doctoral thesis | en_US |
| local.subject.manitoba | no | |
| project.funder.identifier | https://doi.org/10.13039/501100000038 | |
| project.funder.name | Natural Sciences and Engineering Research Council of Canada |