Local Inflammation Precedes Diaphragm Wasting and Fibrotic Remodelling in a Mouse Model of Pancreatic Cancer
ABSTRACT Background Cancer cachexia represents a debilitating muscle wasting condition that is highly prevalent in gastrointestinal cancers, including pancreatic ductal adenocarcinoma (PDAC). Cachexia is estimated to contribute to ~30% of cancer‐related deaths, with deterioration of respiratory musc...
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Wiley
2025-02-01
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| Series: | Journal of Cachexia, Sarcopenia and Muscle |
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| Online Access: | https://doi.org/10.1002/jcsm.13668 |
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| author | Daria Neyroud Andrew C. D'Lugos Enrique J. Trevino Chandler S. Callaway Jacqueline Lamm Orlando Laitano Brittney Poole Michael R. Deyhle Justina Brantley Lam Le Andrew R. Judge Sarah M. Judge |
| author_facet | Daria Neyroud Andrew C. D'Lugos Enrique J. Trevino Chandler S. Callaway Jacqueline Lamm Orlando Laitano Brittney Poole Michael R. Deyhle Justina Brantley Lam Le Andrew R. Judge Sarah M. Judge |
| author_sort | Daria Neyroud |
| collection | DOAJ |
| description | ABSTRACT Background Cancer cachexia represents a debilitating muscle wasting condition that is highly prevalent in gastrointestinal cancers, including pancreatic ductal adenocarcinoma (PDAC). Cachexia is estimated to contribute to ~30% of cancer‐related deaths, with deterioration of respiratory muscles suspected to be a key contributor to cachexia‐associated morbidity and mortality. In recent studies, we identified fibrotic remodelling of respiratory accessory muscles as a key feature of human PDAC cachexia. Methods To gain insight into mechanisms driving respiratory muscle wasting and fibrotic remodelling in response to PDAC, we conducted temporal histological and transcriptomic analyses on diaphragm muscles harvested from mice‐bearing orthotopic murine pancreatic (KPC) tumours at time points reflective of precachexia (D8 and D10), mild–moderate cachexia (D12 and D14) and advanced cachexia (endpoint). Results During the precachexia phase, diaphragms showed significant leukocyte infiltration (+3‐fold to +13‐fold; D8—endpoint vs. Sham, p < 0.05) and transcriptomic enrichment of inflammatory processes associated with tissue injury that remained increased through endpoint. Diaphragm inflammation was followed by increases in PDGFR‐ɑ+ fibroadipogenic progenitors (+2.5 to +3.8‐fold; D10—endpoint vs. Sham, p < 0.05), fibre atrophy (−16% to −24%, D12 to endpoint vs. Sham, p < 0.05), ECM expansion (+1.5 to +1.8‐fold; D14—endpoint vs. Sham, p < 0.05), collagen accumulation (+3.8‐fold; endpoint vs. Sham, p = 0.0013) and reductions in breathing frequency (−55%, p = 0.0074) and diaphragm excursion (−43%, p = 0.0006). These biological processes were supported by changes in the diaphragm transcriptome. Ingenuity pathway analysis predicted factors involved in inflammatory responses to tissue injury, including TGF‐β1, angiotensin and PDGF BB, as top upstream regulators activated in diaphragms prior to and throughout cachexia progression, while PGC‐1α and the insulin receptor were among the top upstream regulators predicted to be suppressed. The transcriptomic dataset further revealed progressive disturbances to networks involved in lipid, glucose and oxidative metabolism, activation of the unfolded protein response and neuromuscular junction remodelling associated with denervation. Conclusions In summary, our data support leukocyte infiltration and expansion of PDGFRα mesenchymal progenitors as early events that precede wasting and fibrotic remodelling of the diaphragm in response to PDAC that may also underlie metabolic disturbances, weakness and respiratory complications. |
| format | Article |
| id | doaj-art-5edaf3db8e614c4b8dc77c4e06bdd541 |
| institution | DOAJ |
| issn | 2190-5991 2190-6009 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Cachexia, Sarcopenia and Muscle |
| spelling | doaj-art-5edaf3db8e614c4b8dc77c4e06bdd5412025-08-20T02:53:13ZengWileyJournal of Cachexia, Sarcopenia and Muscle2190-59912190-60092025-02-01161n/an/a10.1002/jcsm.13668Local Inflammation Precedes Diaphragm Wasting and Fibrotic Remodelling in a Mouse Model of Pancreatic CancerDaria Neyroud0Andrew C. D'Lugos1Enrique J. Trevino2Chandler S. Callaway3Jacqueline Lamm4Orlando Laitano5Brittney Poole6Michael R. Deyhle7Justina Brantley8Lam Le9Andrew R. Judge10Sarah M. Judge11Department of Physical Therapy University of Florida Health Cancer Center Gainesville Florida USADepartment of Physical Therapy University of Florida Health Cancer Center Gainesville Florida USADepartment of Physical Therapy University of Florida Health Cancer Center Gainesville Florida USADepartment of Physical Therapy University of Florida Health Cancer Center Gainesville Florida USADepartment of Physical Therapy University of Florida Health Cancer Center Gainesville Florida USAMyology Institute University of Florida Gainesville Florida USADepartment of Physical Therapy University of Florida Health Cancer Center Gainesville Florida USADepartment of Physical Therapy University of Florida Health Cancer Center Gainesville Florida USADepartment of Physical Therapy University of Florida Health Cancer Center Gainesville Florida USADepartment of Physical Therapy University of Florida Health Cancer Center Gainesville Florida USADepartment of Physical Therapy University of Florida Health Cancer Center Gainesville Florida USADepartment of Physical Therapy University of Florida Health Cancer Center Gainesville Florida USAABSTRACT Background Cancer cachexia represents a debilitating muscle wasting condition that is highly prevalent in gastrointestinal cancers, including pancreatic ductal adenocarcinoma (PDAC). Cachexia is estimated to contribute to ~30% of cancer‐related deaths, with deterioration of respiratory muscles suspected to be a key contributor to cachexia‐associated morbidity and mortality. In recent studies, we identified fibrotic remodelling of respiratory accessory muscles as a key feature of human PDAC cachexia. Methods To gain insight into mechanisms driving respiratory muscle wasting and fibrotic remodelling in response to PDAC, we conducted temporal histological and transcriptomic analyses on diaphragm muscles harvested from mice‐bearing orthotopic murine pancreatic (KPC) tumours at time points reflective of precachexia (D8 and D10), mild–moderate cachexia (D12 and D14) and advanced cachexia (endpoint). Results During the precachexia phase, diaphragms showed significant leukocyte infiltration (+3‐fold to +13‐fold; D8—endpoint vs. Sham, p < 0.05) and transcriptomic enrichment of inflammatory processes associated with tissue injury that remained increased through endpoint. Diaphragm inflammation was followed by increases in PDGFR‐ɑ+ fibroadipogenic progenitors (+2.5 to +3.8‐fold; D10—endpoint vs. Sham, p < 0.05), fibre atrophy (−16% to −24%, D12 to endpoint vs. Sham, p < 0.05), ECM expansion (+1.5 to +1.8‐fold; D14—endpoint vs. Sham, p < 0.05), collagen accumulation (+3.8‐fold; endpoint vs. Sham, p = 0.0013) and reductions in breathing frequency (−55%, p = 0.0074) and diaphragm excursion (−43%, p = 0.0006). These biological processes were supported by changes in the diaphragm transcriptome. Ingenuity pathway analysis predicted factors involved in inflammatory responses to tissue injury, including TGF‐β1, angiotensin and PDGF BB, as top upstream regulators activated in diaphragms prior to and throughout cachexia progression, while PGC‐1α and the insulin receptor were among the top upstream regulators predicted to be suppressed. The transcriptomic dataset further revealed progressive disturbances to networks involved in lipid, glucose and oxidative metabolism, activation of the unfolded protein response and neuromuscular junction remodelling associated with denervation. Conclusions In summary, our data support leukocyte infiltration and expansion of PDGFRα mesenchymal progenitors as early events that precede wasting and fibrotic remodelling of the diaphragm in response to PDAC that may also underlie metabolic disturbances, weakness and respiratory complications.https://doi.org/10.1002/jcsm.13668cancer cachexiainflammatory responsemuscle atrophymuscle fibrosispancreatic cancer |
| spellingShingle | Daria Neyroud Andrew C. D'Lugos Enrique J. Trevino Chandler S. Callaway Jacqueline Lamm Orlando Laitano Brittney Poole Michael R. Deyhle Justina Brantley Lam Le Andrew R. Judge Sarah M. Judge Local Inflammation Precedes Diaphragm Wasting and Fibrotic Remodelling in a Mouse Model of Pancreatic Cancer Journal of Cachexia, Sarcopenia and Muscle cancer cachexia inflammatory response muscle atrophy muscle fibrosis pancreatic cancer |
| title | Local Inflammation Precedes Diaphragm Wasting and Fibrotic Remodelling in a Mouse Model of Pancreatic Cancer |
| title_full | Local Inflammation Precedes Diaphragm Wasting and Fibrotic Remodelling in a Mouse Model of Pancreatic Cancer |
| title_fullStr | Local Inflammation Precedes Diaphragm Wasting and Fibrotic Remodelling in a Mouse Model of Pancreatic Cancer |
| title_full_unstemmed | Local Inflammation Precedes Diaphragm Wasting and Fibrotic Remodelling in a Mouse Model of Pancreatic Cancer |
| title_short | Local Inflammation Precedes Diaphragm Wasting and Fibrotic Remodelling in a Mouse Model of Pancreatic Cancer |
| title_sort | local inflammation precedes diaphragm wasting and fibrotic remodelling in a mouse model of pancreatic cancer |
| topic | cancer cachexia inflammatory response muscle atrophy muscle fibrosis pancreatic cancer |
| url | https://doi.org/10.1002/jcsm.13668 |
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