{"id":{"repo_id":"vt","oai_identifier":"oai:vtechworks.lib.vt.edu:10919/140973"},"canonical_url":"https://search.dev.ndltd.org/etd/vt/oai:vtechworks.lib.vt.edu:10919/140973","repository":{"repo_id":"vt","name":"Virginia Tech","base_url":"https://vtechworks.lib.vt.edu/oai/request"},"display":{"title":"PERM1-Mediated Metabolic Crosstalk Between the Heart and Skeletal Muscle in Pressure Overload-Induced Heart Failure","abstract":"Heart failure is a complex syndrome with high mortality, as nearly 50% of patients die within five years of diagnosis. Among its systemic complications, cardiac cachexia–a condition characterized by severe unintentional weight loss due to cardiac dysfunction– serves as an independent predictor of mortality. The early stage of cachexia involves a vicious cycle between the heart and skeletal muscle driven by metabolic dysregulation; however, its underlying bioenergetics remain unclear. PERM1, a striated muscle-specific regulator of mitochondrial bioenergetics, is highly expressed in the heart and skeletal muscle. We previously demonstrated that PERM1 is downregulated in failing hearts; however, whether its downregulation also occurs in skeletal muscle during the progression of heart failure is unknown. To address this, wild-type mice underwent transverse aortic constriction (TAC) for 8 weeks. Cardiac function and body composition were assessed by echocardiography and NMR, and PERM1 expression and metabolomic profiles were analyzed by Western blotting and gas chromatography-tandem mass spectrometry (GCMS). TAC reduced systolic function and downregulated PERM1 to a comparable extent in both tissues. Global PERM1 knockout (KO) mice exhibited lean mass loss with an increase in adiposity and no change in body weight, indicating sarcopenic phenotype and not cachectic phenotype. Partial loss of PERM1 in heterozygous mice accelerated systolic decline and mortality and modulated metabolomic programs linked to ketone handling, branched and medium chain fatty acid oxidation, malate-aspartate shuttling, amino acid anaplerosis, nitrogen recycling, and membrane/cofactor biosynthesis. In vitro, PERM1 silencing in C2C12 myotubes induced a compensatory shift toward glycolysis. AAV-PERM1 preserved systolic function and remodeled metabolomes modestly in the heart and robustly in skeletal muscle as compared AAV-GFP controls. In summary, this study provides the first coordinated PERM1 downregulation and distinct metabolic alterations, which may contribute to systemic myopathy. These findings highlight PERM1 as a potential regulator of metabolic crosstalk between the heart and skeletal muscle during the progression of heart failure.","abstract_html":"Heart failure is a complex syndrome with high mortality, as nearly 50% of patients die within five years of diagnosis. Among its systemic complications, cardiac cachexia–a condition characterized by severe unintentional weight loss due to cardiac dysfunction– serves as an independent predictor of mortality. The early stage of cachexia involves a vicious cycle between the heart and skeletal muscle driven by metabolic dysregulation; however, its underlying bioenergetics remain unclear. PERM1, a striated muscle-specific regulator of mitochondrial bioenergetics, is highly expressed in the heart and skeletal muscle. We previously demonstrated that PERM1 is downregulated in failing hearts; however, whether its downregulation also occurs in skeletal muscle during the progression of heart failure is unknown. To address this, wild-type mice underwent transverse aortic constriction (TAC) for 8 weeks. Cardiac function and body composition were assessed by echocardiography and NMR, and PERM1 expression and metabolomic profiles were analyzed by Western blotting and gas chromatography-tandem mass spectrometry (GCMS). TAC reduced systolic function and downregulated PERM1 to a comparable extent in both tissues. Global PERM1 knockout (KO) mice exhibited lean mass loss with an increase in adiposity and no change in body weight, indicating sarcopenic phenotype and not cachectic phenotype. Partial loss of PERM1 in heterozygous mice accelerated systolic decline and mortality and modulated metabolomic programs linked to ketone handling, branched and medium chain fatty acid oxidation, malate-aspartate shuttling, amino acid anaplerosis, nitrogen recycling, and membrane/cofactor biosynthesis. In vitro, PERM1 silencing in C2C12 myotubes induced a compensatory shift toward glycolysis. AAV-PERM1 preserved systolic function and remodeled metabolomes modestly in the heart and robustly in skeletal muscle as compared AAV-GFP controls. In summary, this study provides the first coordinated PERM1 downregulation and distinct metabolic alterations, which may contribute to systemic myopathy. These findings highlight PERM1 as a potential regulator of metabolic crosstalk between the heart and skeletal muscle during the progression of heart failure.","abstract_has_math":false,"creators":["Gusinac, Rebekah Thomas"],"institution":"Virginia Tech","degree_name":"Master of Science","degree_level":"masters","degree_discipline":"Translational Biology, Medicine and Health","degree_department":"Graduate School","school":null,"contributors":[],"advisors":[],"committee_chairs":["Warren, Junko"],"committee_members":["Sane, David C.","Sassi, Yassine","Pan, Yuchin Albert","Pfleger, Jessica Mary"],"year":2026,"date_issued":"2026-01-23","date_published":"2026-01-23","updated_at":"2026-07-22T22:20:12Z","subjects":["Heart failure","skeletal muscle","cachexia","sarcopenia","metabolic remodeling","PERM1"],"languages":["en"],"rights":["In Copyright"],"rights_urls":["http://rightsstatements.org/vocab/InC/1.0/"],"identifier_entries":[{"key":"dc:identifier.other","label":"Dc Identifier Other","values":["vt_gsexam:45452"],"render_values":[{"text":"vt_gsexam:45452","href":null,"code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/10919/140973","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.committeechair","label":"Committee Chair","values":["Warren, Junko"]},{"key":"dc:contributor.committeemember","label":"Committee Member","values":["Sane, David C.","Sassi, Yassine","Pan, Yuchin Albert","Pfleger, Jessica Mary"]},{"key":"dc:contributor.department","label":"Department","values":["Graduate School"]},{"key":"dc:creator","label":"Author","values":["Gusinac, Rebekah Thomas"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2026-01-24T09:00:28Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2026-01-24T09:00:28Z"]},{"key":"dc:date.issued","label":"Date","values":["2026-01-23"]},{"key":"dc:publisher","label":"Institution","values":["Virginia Tech"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Translational Biology, Medicine and Health"]},{"key":"thesis:degree_level","label":"Degree Level","values":["masters"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Master of Science"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["Virginia Polytechnic Institute and State University"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Heart failure","skeletal muscle","cachexia","sarcopenia","metabolic remodeling","PERM1"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["In Copyright"]},{"key":"dc:rights.uri","label":"Rights URI","values":["http://rightsstatements.org/vocab/InC/1.0/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.other","label":"Dc Identifier Other","values":["vt_gsexam:45452"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/10919/140973"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Heart failure is a complex syndrome with high mortality, as nearly 50% of patients die within five years of diagnosis. Among its systemic complications, cardiac cachexia–a condition characterized by severe unintentional weight loss due to cardiac dysfunction– serves as an independent predictor of mortality. The early stage of cachexia involves a vicious cycle between the heart and skeletal muscle driven by metabolic dysregulation; however, its underlying bioenergetics remain unclear. PERM1, a striated muscle-specific regulator of mitochondrial bioenergetics, is highly expressed in the heart and skeletal muscle. We previously demonstrated that PERM1 is downregulated in failing hearts; however, whether its downregulation also occurs in skeletal muscle during the progression of heart failure is unknown. To address this, wild-type mice underwent transverse aortic constriction (TAC) for 8 weeks. Cardiac function and body composition were assessed by echocardiography and NMR, and PERM1 expression and metabolomic profiles were analyzed by Western blotting and gas chromatography-tandem mass spectrometry (GCMS). TAC reduced systolic function and downregulated PERM1 to a comparable extent in both tissues. Global PERM1 knockout (KO) mice exhibited lean mass loss with an increase in adiposity and no change in body weight, indicating sarcopenic phenotype and not cachectic phenotype. Partial loss of PERM1 in heterozygous mice accelerated systolic decline and mortality and modulated metabolomic programs linked to ketone handling, branched and medium chain fatty acid oxidation, malate-aspartate shuttling, amino acid anaplerosis, nitrogen recycling, and membrane/cofactor biosynthesis. In vitro, PERM1 silencing in C2C12 myotubes induced a compensatory shift toward glycolysis. AAV-PERM1 preserved systolic function and remodeled metabolomes modestly in the heart and robustly in skeletal muscle as compared AAV-GFP controls. In summary, this study provides the first coordinated PERM1 downregulation and distinct metabolic alterations, which may contribute to systemic myopathy. These findings highlight PERM1 as a potential regulator of metabolic crosstalk between the heart and skeletal muscle during the progression of heart failure."]},{"key":"dc:description.abstractgeneral","label":"General Abstract","values":["Heart failure is a common and deadly health issue with about half of patients dying within five years and it does not only damage the heart. Many patients also lose muscle mass and strength. With some developing cardiac cachexia which is a serious unintended weight loss syndrome that worsens survival. Early in this process, the heart and skeletal muscle appear to drive each other into further trouble through faulty energy use, but the details are not well understood. This study focuses on PERM1, a protein found mainly in the heart and skeletal muscle that helps mitochondria make energy. We asked two questions: how does PERM1 change during heart failure-like stress, and can boosting it protect the heart and muscles? In mice, we created heart failure-like symptoms by tightening the aorta for eight weeks through a surgery called transverse aortic constriction (TAC), then measured heart pumping efficiency by ultrasound, body composition, PERM1 levels by gene and protein level assays, and metabolomic fingerprints of fuels and by-products in the heart and skeletal muscle. We also downregulated PERM1 off in muscle cells grown in the lab and tested a gene therapy style approach that increases PERM1 expression. In mice studies, TAC weakened the heart and lowered PERM1 expression in both the heart and skeletal muscle. Mice completely lacking PERM1 had less lean mass and more body fat without losing overall weight–a pattern more consistent with sarcopenia (loss of muscle) than cachexia. Mice with only one working PERM1 copy declined with more dying more often and showed shifts in how their tissues used fuels. In cultured muscle cells, reducing PERM1 pushes cells to lean more on sugar. By contrast, boosting PERM1 in the mouse heart preserved pumping function and reshaped metabolism modestly in the heart and more strongly in skeletal muscle (toward stronger mitochondrial energy production). Together, these results suggest that PERM1 helps coordinate energy use between the heart and skeletal muscle in heart failure and highlight PERM1 as a promising target for future therapies."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Master of Science"]},{"key":"dc:format.medium","label":"Dc Format Medium","values":["ETD"]},{"key":"dc:title","label":"Title","values":["PERM1-Mediated Metabolic Crosstalk Between the Heart and Skeletal Muscle in Pressure Overload-Induced Heart Failure"]}]}],"canonical_facts":{"dc:contributor.committeechair":["Warren, Junko"],"dc:contributor.committeemember":["Sane, David C.","Sassi, Yassine","Pan, Yuchin Albert","Pfleger, Jessica Mary"],"dc:contributor.department":["Graduate School"],"dc:creator":["Gusinac, Rebekah Thomas"],"dc:date.accessioned":["2026-01-24T09:00:28Z"],"dc:date.available":["2026-01-24T09:00:28Z"],"dc:date.issued":["2026-01-23"],"dc:description.abstract":["Heart failure is a complex syndrome with high mortality, as nearly 50% of patients die within five years of diagnosis. Among its systemic complications, cardiac cachexia–a condition characterized by severe unintentional weight loss due to cardiac dysfunction– serves as an independent predictor of mortality. The early stage of cachexia involves a vicious cycle between the heart and skeletal muscle driven by metabolic dysregulation; however, its underlying bioenergetics remain unclear. PERM1, a striated muscle-specific regulator of mitochondrial bioenergetics, is highly expressed in the heart and skeletal muscle. We previously demonstrated that PERM1 is downregulated in failing hearts; however, whether its downregulation also occurs in skeletal muscle during the progression of heart failure is unknown. To address this, wild-type mice underwent transverse aortic constriction (TAC) for 8 weeks. Cardiac function and body composition were assessed by echocardiography and NMR, and PERM1 expression and metabolomic profiles were analyzed by Western blotting and gas chromatography-tandem mass spectrometry (GCMS). TAC reduced systolic function and downregulated PERM1 to a comparable extent in both tissues. Global PERM1 knockout (KO) mice exhibited lean mass loss with an increase in adiposity and no change in body weight, indicating sarcopenic phenotype and not cachectic phenotype. Partial loss of PERM1 in heterozygous mice accelerated systolic decline and mortality and modulated metabolomic programs linked to ketone handling, branched and medium chain fatty acid oxidation, malate-aspartate shuttling, amino acid anaplerosis, nitrogen recycling, and membrane/cofactor biosynthesis. In vitro, PERM1 silencing in C2C12 myotubes induced a compensatory shift toward glycolysis. AAV-PERM1 preserved systolic function and remodeled metabolomes modestly in the heart and robustly in skeletal muscle as compared AAV-GFP controls. In summary, this study provides the first coordinated PERM1 downregulation and distinct metabolic alterations, which may contribute to systemic myopathy. These findings highlight PERM1 as a potential regulator of metabolic crosstalk between the heart and skeletal muscle during the progression of heart failure."],"dc:description.abstractgeneral":["Heart failure is a common and deadly health issue with about half of patients dying within five years and it does not only damage the heart. Many patients also lose muscle mass and strength. With some developing cardiac cachexia which is a serious unintended weight loss syndrome that worsens survival. Early in this process, the heart and skeletal muscle appear to drive each other into further trouble through faulty energy use, but the details are not well understood. This study focuses on PERM1, a protein found mainly in the heart and skeletal muscle that helps mitochondria make energy. We asked two questions: how does PERM1 change during heart failure-like stress, and can boosting it protect the heart and muscles? In mice, we created heart failure-like symptoms by tightening the aorta for eight weeks through a surgery called transverse aortic constriction (TAC), then measured heart pumping efficiency by ultrasound, body composition, PERM1 levels by gene and protein level assays, and metabolomic fingerprints of fuels and by-products in the heart and skeletal muscle. We also downregulated PERM1 off in muscle cells grown in the lab and tested a gene therapy style approach that increases PERM1 expression. In mice studies, TAC weakened the heart and lowered PERM1 expression in both the heart and skeletal muscle. Mice completely lacking PERM1 had less lean mass and more body fat without losing overall weight–a pattern more consistent with sarcopenia (loss of muscle) than cachexia. Mice with only one working PERM1 copy declined with more dying more often and showed shifts in how their tissues used fuels. In cultured muscle cells, reducing PERM1 pushes cells to lean more on sugar. By contrast, boosting PERM1 in the mouse heart preserved pumping function and reshaped metabolism modestly in the heart and more strongly in skeletal muscle (toward stronger mitochondrial energy production). Together, these results suggest that PERM1 helps coordinate energy use between the heart and skeletal muscle in heart failure and highlight PERM1 as a promising target for future therapies."],"dc:description.degree":["Master of Science"],"dc:format.medium":["ETD"],"dc:identifier.other":["vt_gsexam:45452"],"dc:identifier.uri":["https://hdl.handle.net/10919/140973"],"dc:language.iso":["en"],"dc:publisher":["Virginia Tech"],"dc:rights":["In Copyright"],"dc:rights.uri":["http://rightsstatements.org/vocab/InC/1.0/"],"dc:subject":["Heart failure","skeletal muscle","cachexia","sarcopenia","metabolic remodeling","PERM1"],"dc:title":["PERM1-Mediated Metabolic Crosstalk Between the Heart and Skeletal Muscle in Pressure Overload-Induced Heart Failure"],"dc:type":["Thesis"],"thesis:degree_discipline":["Translational Biology, Medicine and Health"],"thesis:degree_level":["masters"],"thesis:degree_name":["Master of Science"],"thesis:institution_name":["Virginia Polytechnic Institute and State University"]},"updated_at":"2026-07-22T22:20:12Z"}