The impact of energetic stress, sex differences, and menstrual cycle on unconventional regulators of mitochondrial biogenesis in human skeletal muscle
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Authors
Soares Menezes, Eveline
Date
2024-12-23
Type
thesis
Language
eng
Keyword
Muscle remodeling , High-intensity aerobic exercise , Transcriptional regulators , Skeletal muscle adaptation , Oxidative metabolism , Mitochondrial content
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Abstract
Despite the well-established role of the transcriptional co-activator PGC-1α in driving mitochondrial biogenesis in skeletal muscle following exercise, this process is likely coordinated by a broader network of transcriptional regulators. This dissertation aimed to elucidate the role of unconventional regulators of mitochondrial biogenesis in human skeletal muscle in response to different physiological conditions, including acute and chronic energetic stress, sex differences, and menstrual cycle. We first investigated the impact of acute energetic stress – high-intense interval exercise (HIIE) and fasting – on unconventional genes involved in the regulation of mitochondrial biogenesis in human skeletal muscle, including ERRγ, PPARβ, NR1D1, NR4A1, and TFEB. We found that NR4A1 and NR1D1 are downregulated in response to a short-term fasting period. Next, we reviewed the literature to understand the role of PERM1 – another emerging regulator of mitochondrial biogenesis – in various organisms, tissues, and cellular functions, highlighting its putative role in the regulation of skeletal muscle mitochondrial biogenesis. Then we characterized the regulation of the PERM1 pathway and its target genes/proteins in human skeletal muscle in response to multiple energetic stresses (i.e.: fasting, exercise) and physiological conditions (i.e.: sex-differences, menstrual cycle phases). We found that HIIE up-regulates the activation of p38MAPK and the expression of PGC-1α, PERM1, and that high-intense interval training (HIIT) enhances the protein content of PERM1 isoform 2 protein and CKMT2. We also observed that PERM1 is localized in the periphery of the cells, perinuclear. Finally, we demonstrated that PERM1 total protein content is more abundant in males skeletal muscle compared to females, and that GLUT4 is upregulated during high-estradiol (LF) phase of the menstrual cycle without any associated changes in PERM1 or other PERM1 targets. The findings of this dissertation advance our knowledge of PERM1’s role under various energetic stresses and sex-specific differences in baseline protein expression, highlighting its potential as a target for future research in field of mitochondrial biogenesis in human skeletal muscle.
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ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.
Attribution-NoDerivatives 4.0 International