Role of mitophagy in pancreatic cancer cachexia-induced muscle atrophy
10.16016/j.2097-0927.202410021
- VernacularTitle:线粒体自噬对胰腺癌恶病质肌萎缩的作用研究
- Author:
Yijie WANG
1
;
Jianjun LI
;
Xuesong WANG
;
Yan DONG
;
Houjie LIANG
Author Information
1. 陆军军医大学(第三军医大学)第一附属医院肿瘤科
- Keywords:
cachexia;
mitophagy;
pancreatic cancer;
muscle atrophy
- From:
Journal of Army Medical University
2025;47(11):1190-1198
- CountryChina
- Language:Chinese
-
Abstract:
Objective To explore the role of mitophagy in pancreatic cancer cachexia-induced muscle atrophy and its underlying mechanism.Methods Six male C57BL/6J mice(8 weeks old,weighing 20～30 g)were equally and randomly divided into a control group(intrapancreatic injection of normal saline)and a cachexia group(orthotopic pancreatic injection of KPC1199 cells).After successful model establishment,gastrocnemius muscles were harvested for transmission electron microscopy(TEM)to assess mitochondrial ultrastructure.Western blotting was performed to quantify mitochondrial respiratory chain complexes(Ⅰ～Ⅳ)and autophagy-related proteins,while immunofluorescence staining was conducted to evaluate mitochondrial-lysosomal colocalization.In in vitro experiments,C2C12 myoblasts were differentiated into myotubes,and then divided into a control group(standard culture)and a cachexia group(co-cultured with KPC1199 cells for 48 h using transwell chambers).Mitochondrial-lysosomal colocalization and autophagy-related protein expression were analyzed with immunofluorescence assay and Western blotting.The mitochondrial division inhibitor Mdivi-1(20 μmol/L)was added to the co-culture system to assess its myotube diameter.Results Compared to the control mice,the cachectic mice exhibited mitochondrial swelling,reduced cristae density,and significantly increased mitochondrial-lysosomal colocalization in gastrocnemius muscle(P<0.05).Western blotting revealed the expression levels of mitochondrial respiratory chain proteins complexⅠ(1.00±0.04 vs 0.51±0.04,P<0.05),complexⅡ(1.00±0.13 vs 0.73±0.15,P<0.05),complexⅢ(1.00±0.20 vs 0.64±0.01,P<0.05),complexⅣ(1.00±0.06 vs 0.65±0.02,P<0.05)and PGC1α(1.00±0.03 vs 0.62±0.06,P<0.05)were decreased,and the levels of mitophagy markers,LC3-Ⅰ/Ⅱ(1.00±0.14 vs 1.65±0.25,P<0.05),PINK1(1.00±0.11 vs 1.51±0.05,P<0.05),and BNIP3(1.00±0.22 vs 2.02±0.10,P<0.05)were elevated when compared to the control.In the C2C12 myotube model,tumor cell co-culture increased mitochondrial-lysosomal colocalization and upregulated mitophagy-related protein expression(P<0.05),consistent with the in vivo findings.Mdivi-1 treatment increased myotube diameter from 220.6±35.5 μm to 315.0±39.1 μm(R2=0.666 5,P<0.05).Conclusion Mitophagy is activated in pancreatic cancer cachexia-induced muscle atrophy.Inhibiting mitophagy can effectively alleviate muscle atrophy induced by pancreatic cancer cachexia.
