4.6 Article

Inflammation and Wasting of Skeletal Muscles in Kras-p53-Mutant Mice with Intraepithelial Neoplasia and Pancreatic Cancer-When Does Cachexia Start?

期刊

CELLS
卷 11, 期 10, 页码 -

出版社

MDPI
DOI: 10.3390/cells11101607

关键词

cancer cachexia; muscle atrophy; weight loss; sarcopenia; cytokines; gastrointestinal cancer

资金

  1. University Clinics of Giessen and Marburg (UKGM) [44/2011]

向作者/读者索取更多资源

Skeletal muscle wasting is a significant issue in patients with pancreatic ductal adenocarcinoma (PDAC), and this study aimed to identify the factors responsible for muscle wasting. The researchers found that muscle wasting was associated with PDAC development and local inflammation, without affecting microcirculation, innervation, or mitochondria. Surprisingly, markers of inflammation, protein hydrolysis, and increased amino acid and glutathione levels were also detected in mice with precancerous lesions.
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-Kras(G12D/+); LSL-TrP53(R172H/+); 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.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.6
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据