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postgraduate thesis: Role of exercise-induced brain-derived neurotrophic factor in muscle adaptations
Title | Role of exercise-induced brain-derived neurotrophic factor in muscle adaptations |
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Authors | |
Issue Date | 2022 |
Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
Citation | Chan, W. S. [陳穎旋]. (2022). Role of exercise-induced brain-derived neurotrophic factor in muscle adaptations. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. |
Abstract | The increasing global prevalence of physical inactivity is associated with a growing population of obesity and its related metabolic syndromes. Obesity is caused by excessive fat accumulation due to energy surplus. Regular exercise helps maintain energy homeostasis through upregulating fatty acid oxidation (FAO) in the mitochondria. Mitochondria are dynamic organelles that are constantly replaced when damaged by reactive oxygen species generated during respiration. Mitochondrial recycling is a quality control system to maintain the cellular oxidative capacity. Exercise is known to upregulate mitochondrial turnover to face the energy demand. Recently, studies have shown that exercise-induced myokines exert hormonal regulations on mitochondrial recycling. This study identifies the brain-derived neurotrophic factor (BDNF) as a moderate-intensity exercise-induced myokine. Our laboratory has previously reported that BDNF can activate AMPK, but the physiological significance of this pathway in exercise remains unexplored. We hypothesized that exercise-induced BDNF activates AMPK to upregulate mitochondrial recycling and enhance mitochondrial FAO as a muscle adaptation to endurance exercise. Thus, the muscle-specific Bdnf knockout (MBKO) mice were used to investigate the role of muscle BDNF in promoting muscle recovery and adaptation after exercise. Our results showed that MBKO mice had comparable running time and
II
distance to the control BDNF F/F mice on the treadmill exhaustion test, indicating similar muscle endurance. Exercise-induced AMPK phosphorylation was absent in MBKO mice, suggesting a possibly compromised mitophagy as AMPK-provoked ULK1 phosphorylations are required for autophagosome formation to facilitate mitochondria removal. Fatty acid uptake was also slightly diminished in the MBKO muscles. Because these abnormalities did not affect the muscle exercise performance in sedentary mice, we introduced the mice to a 4-week exercise training to study the significance of BDNF in chronic exercise-induced muscle adaptations. Muscle endurance was only improved in BDNF F/F but not in MBKO mice after exercise training. This phenotypic difference was a consequence of diminished mitochondrial dynamics in the MBKO muscles that resulted in insufficient clearance of ROS-damaged mitochondria and reduced FAO capacity. In addition to identifying the functions of muscle-derived BDNF in exercise, we also explored the mechanism of BDNF-induced AMPK activation. We found that BDNF-TrkB interaction triggered an intracellular calcium influx via the PLCγ signaling and activated calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ), which then phosphorylated AMPK in cultured myotubes. Despite the potential of BDNF in enhancing mitochondrial function, its poor pharmacokinetics hinders its clinical application. Thus, we used the BDNF mimetic, 7,8-dihydroxyflavone, dissolved in drinking water to treat sedentary C57BL/6N mice and found that it upregulated mitochondrial turnover even without exercise. Collectively, our results suggest that BDNF is critical in mediating exercise-enhanced mitochondrial oxidative capacity, and its mimetic has a great therapeutic potential to improve energy homeostasis in people with a sedentary lifestyle. |
Degree | Doctor of Philosophy |
Subject | Exercise - Physiological aspects Nerve growth factors |
Dept/Program | Biological Sciences |
Persistent Identifier | http://hdl.handle.net/10722/325705 |
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Chan, Wing Suen | - |
dc.contributor.author | 陳穎旋 | - |
dc.date.accessioned | 2023-03-02T16:32:10Z | - |
dc.date.available | 2023-03-02T16:32:10Z | - |
dc.date.issued | 2022 | - |
dc.identifier.citation | Chan, W. S. [陳穎旋]. (2022). Role of exercise-induced brain-derived neurotrophic factor in muscle adaptations. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. | - |
dc.identifier.uri | http://hdl.handle.net/10722/325705 | - |
dc.description.abstract | The increasing global prevalence of physical inactivity is associated with a growing population of obesity and its related metabolic syndromes. Obesity is caused by excessive fat accumulation due to energy surplus. Regular exercise helps maintain energy homeostasis through upregulating fatty acid oxidation (FAO) in the mitochondria. Mitochondria are dynamic organelles that are constantly replaced when damaged by reactive oxygen species generated during respiration. Mitochondrial recycling is a quality control system to maintain the cellular oxidative capacity. Exercise is known to upregulate mitochondrial turnover to face the energy demand. Recently, studies have shown that exercise-induced myokines exert hormonal regulations on mitochondrial recycling. This study identifies the brain-derived neurotrophic factor (BDNF) as a moderate-intensity exercise-induced myokine. Our laboratory has previously reported that BDNF can activate AMPK, but the physiological significance of this pathway in exercise remains unexplored. We hypothesized that exercise-induced BDNF activates AMPK to upregulate mitochondrial recycling and enhance mitochondrial FAO as a muscle adaptation to endurance exercise. Thus, the muscle-specific Bdnf knockout (MBKO) mice were used to investigate the role of muscle BDNF in promoting muscle recovery and adaptation after exercise. Our results showed that MBKO mice had comparable running time and II distance to the control BDNF F/F mice on the treadmill exhaustion test, indicating similar muscle endurance. Exercise-induced AMPK phosphorylation was absent in MBKO mice, suggesting a possibly compromised mitophagy as AMPK-provoked ULK1 phosphorylations are required for autophagosome formation to facilitate mitochondria removal. Fatty acid uptake was also slightly diminished in the MBKO muscles. Because these abnormalities did not affect the muscle exercise performance in sedentary mice, we introduced the mice to a 4-week exercise training to study the significance of BDNF in chronic exercise-induced muscle adaptations. Muscle endurance was only improved in BDNF F/F but not in MBKO mice after exercise training. This phenotypic difference was a consequence of diminished mitochondrial dynamics in the MBKO muscles that resulted in insufficient clearance of ROS-damaged mitochondria and reduced FAO capacity. In addition to identifying the functions of muscle-derived BDNF in exercise, we also explored the mechanism of BDNF-induced AMPK activation. We found that BDNF-TrkB interaction triggered an intracellular calcium influx via the PLCγ signaling and activated calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ), which then phosphorylated AMPK in cultured myotubes. Despite the potential of BDNF in enhancing mitochondrial function, its poor pharmacokinetics hinders its clinical application. Thus, we used the BDNF mimetic, 7,8-dihydroxyflavone, dissolved in drinking water to treat sedentary C57BL/6N mice and found that it upregulated mitochondrial turnover even without exercise. Collectively, our results suggest that BDNF is critical in mediating exercise-enhanced mitochondrial oxidative capacity, and its mimetic has a great therapeutic potential to improve energy homeostasis in people with a sedentary lifestyle. | - |
dc.language | eng | - |
dc.publisher | The University of Hong Kong (Pokfulam, Hong Kong) | - |
dc.relation.ispartof | HKU Theses Online (HKUTO) | - |
dc.rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject.lcsh | Exercise - Physiological aspects | - |
dc.subject.lcsh | Nerve growth factors | - |
dc.title | Role of exercise-induced brain-derived neurotrophic factor in muscle adaptations | - |
dc.type | PG_Thesis | - |
dc.description.thesisname | Doctor of Philosophy | - |
dc.description.thesislevel | Doctoral | - |
dc.description.thesisdiscipline | Biological Sciences | - |
dc.description.nature | published_or_final_version | - |
dc.date.hkucongregation | 2022 | - |
dc.identifier.mmsid | 991044649995903414 | - |