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Inflammation and Wasting of Skeletal Muscles in Kras-p53-Mutant Mice with Intraepithelial Neoplasia and Pancreatic Cancer — When Does Cachexia Start?
Skeletal muscle wasting critically impairs the survival and quality of life in patients with pancreatic ductal adenocarcinoma (PDAC). To identify the local factors initiating muscle wasting, we studied inflammation, fiber cross-sectional area (CSA), composition, amino acid metabolism and capillar...
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| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Philipps-Universität Marburg
2023
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| Subjects: | |
| Online Access: | PDF Full Text |
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| Summary: | Skeletal muscle wasting critically impairs the survival and quality of life in patients with
pancreatic ductal adenocarcinoma (PDAC). To identify the local factors initiating muscle wasting,
we studied inflammation, fiber cross-sectional area (CSA), composition, amino acid metabolism
and capillarization, as well as the integrity of neuromuscular junctions (NMJ, pre-/postsynaptic
co-staining) and mitochondria (electron microscopy) in the hindlimb muscle of LSL-KrasG12D/+;
LSL-TrP53R172H/+; Pdx1-Cre mice with intraepithelial-neoplasia (PanIN) 1-3 and PDAC, compared
to wild-type mice (WT). Significant decreases in fiber CSA occurred with PDAC but not with
PanIN 1-3, compared to WT: These were found in the gastrocnemius (type 2x: ?20.0%) and soleus
(type 2a: ?21.0%, type 1: ?14.2%) muscle with accentuation in the male soleus (type 2a: ?24.8%,
type 1: ?17.4%) and female gastrocnemius muscle (?29.6%). Significantly higher densities of endomysial
CD68+ and cyclooxygenase-2+ (COX2+) cells were detected in mice with PDAC, compared
to WT mice. Surprisingly, CD68+ and COX2+ cell densities were also higher in mice with PanIN
1-3 in both muscles. Significant positive correlations existed between muscular and hepatic CD68+
or COX2+ cell densities. Moreover, in the gastrocnemius muscle, suppressor-of-cytokine-3 (SOCS3)
expressions was upregulated >2.7-fold with PanIN 1A-3 and PDAC. The intracellular pools of proteinogenic
amino acids and glutathione significantly increased with PanIN 1A-3 compared to WT.
Capillarization, NMJ, and mitochondrial ultrastructure remained unchanged with PanIN or PDAC. In
conclusion, the onset of fiber atrophy coincides with the manifestation of PDAC and high-grade local
(and hepatic) inflammatory infiltration without compromised microcirculation, innervation or mitochondria.
Surprisingly, muscular and hepatic inflammation, SOCS3 upregulation and (proteolytic)
increases in free amino acids and glutathione were already detectable in mice with precancerous
PanINs. Studies of initial local triggers and defense mechanisms regarding cachexia are warranted
for targeted anti-inflammatory prevention. |
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| Item Description: | Gefördert durch den Open-Access-Publikationsfonds der UB Marburg. |
| Physical Description: | 27 Pages |
| DOI: | 10.3390/cells11101607 |