{"id":{"repo_id":"brock","oai_identifier":"oai:brocku.scholaris.ca:10464/19590"},"canonical_url":"https://search.dev.ndltd.org/etd/brock/oai:brocku.scholaris.ca:10464/19590","repository":{"repo_id":"brock","name":"Brock University","base_url":"https://brocku.scholaris.ca/server/oai/request"},"display":{"title":"Partial GSK3 knockdown improves muscle performance in mdx mice: investigating the cellular mechanisms","abstract":"Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease caused by an X-linked mutation to the dystrophin gene that primarily affects boys. The absence of functional dystrophin protein leads to muscle wasting and weakness that progressively worsens over time with affected boys typically being wheelchair-bound by their teenage years, living a shortened lifespan of 30-40 years. Today, most treatment plans are focused on improving quality of life and preserving muscle strength for as long as possible, with glucocorticoids being the current standard of care. While effective in delaying the loss of ambulation, the side effects associated with these medications often lead to drug discontinuation. Our lab has recently shown that knocking down the enzyme glycogen synthase kinase 3 (GSK3) improved muscle strength and fatigue resistance in a preclinical model for DMD, the mdx mouse. However, the exact cellular mechanisms leading to these benefits remain unknown and is the purpose of the present thesis. To this end, male muscle-specific GSK3 knockdown mice (C57BL/6J background) were bred with female homozygous D2 mdx mice to produce 1) mdx mice with partial (30-40%) muscle-specific GSK3 knockdown (mdx/GSK3KD) and 2) mdx mice with GSK3 intact (flox control). To determine how GSK3 knockdown improves muscle strength and endurance, muscle glycogen content, fibre type composition, calcium handling, histopathology, and oxidative stress was assessed in extensor digitorum longus muscle at 4-6 weeks and 10-14 weeks of age, with glycogen content also being measured in the soleus as well. RNASeq analysis was conducted in gastrocnemius muscles obtained from mdx and mdx/GSK3KD mice. We saw an increase in glycogen content in both the EDL and soleus, an increase in the proportion of oxidative fibre types, along with a reduction in histopathology, and oxidative stress in the mdx/GSK3KD mice, with no change to maximal SERCA activity. RNASeq analysis corroborated findings of lowered fibrosis with significant downregulated genes associated with the extracellular matrix and collagen-containing extracellular matrix gene ontology pathways. In conclusion, this thesis provided a deeper understanding of the mechanisms leading to the improvement in muscle health in mdx/GSK3KD mice, adding further evidence in support of targeting GSK3 for DMD.","abstract_html":"Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease caused by an X-linked mutation to the dystrophin gene that primarily affects boys. The absence of functional dystrophin protein leads to muscle wasting and weakness that progressively worsens over time with affected boys typically being wheelchair-bound by their teenage years, living a shortened lifespan of 30-40 years. Today, most treatment plans are focused on improving quality of life and preserving muscle strength for as long as possible, with glucocorticoids being the current standard of care. While effective in delaying the loss of ambulation, the side effects associated with these medications often lead to drug discontinuation. Our lab has recently shown that knocking down the enzyme glycogen synthase kinase 3 (GSK3) improved muscle strength and fatigue resistance in a preclinical model for DMD, the mdx mouse. However, the exact cellular mechanisms leading to these benefits remain unknown and is the purpose of the present thesis. To this end, male muscle-specific GSK3 knockdown mice (C57BL/6J background) were bred with female homozygous D2 mdx mice to produce 1) mdx mice with partial (30-40%) muscle-specific GSK3 knockdown (mdx/GSK3KD) and 2) mdx mice with GSK3 intact (flox control). To determine how GSK3 knockdown improves muscle strength and endurance, muscle glycogen content, fibre type composition, calcium handling, histopathology, and oxidative stress was assessed in extensor digitorum longus muscle at 4-6 weeks and 10-14 weeks of age, with glycogen content also being measured in the soleus as well. RNASeq analysis was conducted in gastrocnemius muscles obtained from mdx and mdx/GSK3KD mice. We saw an increase in glycogen content in both the EDL and soleus, an increase in the proportion of oxidative fibre types, along with a reduction in histopathology, and oxidative stress in the mdx/GSK3KD mice, with no change to maximal SERCA activity. RNASeq analysis corroborated findings of lowered fibrosis with significant downregulated genes associated with the extracellular matrix and collagen-containing extracellular matrix gene ontology pathways. In conclusion, this thesis provided a deeper understanding of the mechanisms leading to the improvement in muscle health in mdx/GSK3KD mice, adding further evidence in support of targeting GSK3 for DMD.","abstract_has_math":false,"creators":["Marais,Amélie Annie Thérèsa"],"institution":"Brock University","degree_name":"M.Sc. Applied Health Sciences","degree_level":"Masters","degree_discipline":"Faculty of Applied Health Sciences","degree_department":"Applied Health Sciences Program","school":null,"contributors":[],"advisors":["Fajardo, Val Andrew"],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-09-03T20:13:55Z","date_published":"2025-09-03T20:13:55Z","updated_at":"2026-07-24T01:23:04Z","subjects":["MEDICINE::Physiology and pharmacology::Physiology::Laboratory animal science","NATURAL SCIENCES::Biology::Organism biology::Animal physiology","MEDICINE::Morphology, cell biology, pathology::Morphology::Histology"],"languages":["eng"],"rights":["Attribution-NonCommercial-NoDerivatives 4.0 International"],"rights_urls":["http://creativecommons.org/licenses/by-nc-nd/4.0/"],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/10464/19590","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Fajardo, Val Andrew"]},{"key":"dc:contributor.department","label":"Department","values":["Applied Health Sciences Program"]},{"key":"dc:creator","label":"Author","values":["Marais,Amélie Annie Thérèsa"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2025-09-03T20:13:55Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2025-09-03T20:13:55Z"]},{"key":"dc:date.issued","label":"Date","values":["2025-09-03T20:13:55Z"]},{"key":"dc:publisher","label":"Institution","values":["Brock University"]},{"key":"dc:type","label":"Dc Type","values":["Electronic Thesis or Dissertation"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Faculty of Applied Health Sciences"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Masters"]},{"key":"thesis:degree_name","label":"Degree Name","values":["M.Sc. Applied Health Sciences"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["MEDICINE::Physiology and pharmacology::Physiology::Laboratory animal science","NATURAL SCIENCES::Biology::Organism biology::Animal physiology","MEDICINE::Morphology, cell biology, pathology::Morphology::Histology"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Attribution-NonCommercial-NoDerivatives 4.0 International"]},{"key":"dc:rights.uri","label":"Rights URI","values":["http://creativecommons.org/licenses/by-nc-nd/4.0/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/10464/19590"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease caused by an X-linked mutation to the dystrophin gene that primarily affects boys. The absence of functional dystrophin protein leads to muscle wasting and weakness that progressively worsens over time with affected boys typically being wheelchair-bound by their teenage years, living a shortened lifespan of 30-40 years. Today, most treatment plans are focused on improving quality of life and preserving muscle strength for as long as possible, with glucocorticoids being the current standard of care. While effective in delaying the loss of ambulation, the side effects associated with these medications often lead to drug discontinuation. Our lab has recently shown that knocking down the enzyme glycogen synthase kinase 3 (GSK3) improved muscle strength and fatigue resistance in a preclinical model for DMD, the mdx mouse. However, the exact cellular mechanisms leading to these benefits remain unknown and is the purpose of the present thesis. To this end, male muscle-specific GSK3 knockdown mice (C57BL/6J background) were bred with female homozygous D2 mdx mice to produce 1) mdx mice with partial (30-40%) muscle-specific GSK3 knockdown (mdx/GSK3KD) and 2) mdx mice with GSK3 intact (flox control). To determine how GSK3 knockdown improves muscle strength and endurance, muscle glycogen content, fibre type composition, calcium handling, histopathology, and oxidative stress was assessed in extensor digitorum longus muscle at 4-6 weeks and 10-14 weeks of age, with glycogen content also being measured in the soleus as well. RNASeq analysis was conducted in gastrocnemius muscles obtained from mdx and mdx/GSK3KD mice. We saw an increase in glycogen content in both the EDL and soleus, an increase in the proportion of oxidative fibre types, along with a reduction in histopathology, and oxidative stress in the mdx/GSK3KD mice, with no change to maximal SERCA activity. RNASeq analysis corroborated findings of lowered fibrosis with significant downregulated genes associated with the extracellular matrix and collagen-containing extracellular matrix gene ontology pathways. In conclusion, this thesis provided a deeper understanding of the mechanisms leading to the improvement in muscle health in mdx/GSK3KD mice, adding further evidence in support of targeting GSK3 for DMD."]},{"key":"dc:title","label":"Title","values":["Partial GSK3 knockdown improves muscle performance in mdx mice: investigating the cellular mechanisms"]}]}],"canonical_facts":{"dc:contributor.advisor":["Fajardo, Val Andrew"],"dc:contributor.department":["Applied Health Sciences Program"],"dc:creator":["Marais,Amélie Annie Thérèsa"],"dc:date.accessioned":["2025-09-03T20:13:55Z"],"dc:date.available":["2025-09-03T20:13:55Z"],"dc:date.issued":["2025-09-03T20:13:55Z"],"dc:description.abstract":["Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease caused by an X-linked mutation to the dystrophin gene that primarily affects boys. The absence of functional dystrophin protein leads to muscle wasting and weakness that progressively worsens over time with affected boys typically being wheelchair-bound by their teenage years, living a shortened lifespan of 30-40 years. Today, most treatment plans are focused on improving quality of life and preserving muscle strength for as long as possible, with glucocorticoids being the current standard of care. While effective in delaying the loss of ambulation, the side effects associated with these medications often lead to drug discontinuation. Our lab has recently shown that knocking down the enzyme glycogen synthase kinase 3 (GSK3) improved muscle strength and fatigue resistance in a preclinical model for DMD, the mdx mouse. However, the exact cellular mechanisms leading to these benefits remain unknown and is the purpose of the present thesis. To this end, male muscle-specific GSK3 knockdown mice (C57BL/6J background) were bred with female homozygous D2 mdx mice to produce 1) mdx mice with partial (30-40%) muscle-specific GSK3 knockdown (mdx/GSK3KD) and 2) mdx mice with GSK3 intact (flox control). To determine how GSK3 knockdown improves muscle strength and endurance, muscle glycogen content, fibre type composition, calcium handling, histopathology, and oxidative stress was assessed in extensor digitorum longus muscle at 4-6 weeks and 10-14 weeks of age, with glycogen content also being measured in the soleus as well. RNASeq analysis was conducted in gastrocnemius muscles obtained from mdx and mdx/GSK3KD mice. We saw an increase in glycogen content in both the EDL and soleus, an increase in the proportion of oxidative fibre types, along with a reduction in histopathology, and oxidative stress in the mdx/GSK3KD mice, with no change to maximal SERCA activity. RNASeq analysis corroborated findings of lowered fibrosis with significant downregulated genes associated with the extracellular matrix and collagen-containing extracellular matrix gene ontology pathways. In conclusion, this thesis provided a deeper understanding of the mechanisms leading to the improvement in muscle health in mdx/GSK3KD mice, adding further evidence in support of targeting GSK3 for DMD."],"dc:identifier.uri":["https://hdl.handle.net/10464/19590"],"dc:language.iso":["eng"],"dc:publisher":["Brock University"],"dc:rights":["Attribution-NonCommercial-NoDerivatives 4.0 International"],"dc:rights.uri":["http://creativecommons.org/licenses/by-nc-nd/4.0/"],"dc:subject":["MEDICINE::Physiology and pharmacology::Physiology::Laboratory animal science","NATURAL SCIENCES::Biology::Organism biology::Animal physiology","MEDICINE::Morphology, cell biology, pathology::Morphology::Histology"],"dc:title":["Partial GSK3 knockdown improves muscle performance in mdx mice: investigating the cellular mechanisms"],"dc:type":["Electronic Thesis or Dissertation"],"thesis:degree_discipline":["Faculty of Applied Health Sciences"],"thesis:degree_level":["Masters"],"thesis:degree_name":["M.Sc. Applied Health Sciences"]},"updated_at":"2026-07-24T01:23:04Z"}