Complement pathway activation mediates pancreatic cancer–induced muscle wasting and pathological remodeling
Andrew C. D’Lugos, Jeremy B. Ducharme, Chandler S. Callaway, Jose G. Trevino, Carl Atkinson, Sarah M. Judge, Andrew R. Judge
Andrew C. D’Lugos, Jeremy B. Ducharme, Chandler S. Callaway, Jose G. Trevino, Carl Atkinson, Sarah M. Judge, Andrew R. Judge
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Research Article Muscle biology Oncology

Complement pathway activation mediates pancreatic cancer–induced muscle wasting and pathological remodeling

Abstract

Cancer cachexia is a multifactorial condition characterized by skeletal muscle wasting that impairs quality of life and longevity for many cancer patients. A greater understanding of the molecular etiology of this condition is needed for effective therapies to be developed. We performed a quantitative proteomic analysis of skeletal muscle from cachectic pancreatic ductal adenocarcinoma (PDAC) patients and non-cancer controls, followed by immunohistochemical analyses of muscle cross sections. These data provide evidence of a local inflammatory response in muscles of cachectic PDAC patients, including an accumulation of plasma proteins and recruitment of immune cells into muscle that may promote the pathological remodeling of muscle. Our data further support the complement system as a potential mediator of these processes, which we tested by injecting murine pancreatic cancer cells into wild-type mice and mice with genetic deletion of the central complement component 3 (C3–/– mice). Compared with wild-type mice, C3–/– mice showed attenuated tumor-induced muscle wasting and dysfunction and reduced immune cell recruitment and fibrotic remodeling of muscle. These studies demonstrate that complement activation contributes to the skeletal muscle pathology and dysfunction in PDAC, suggesting that the complement system may possess therapeutic potential in preserving skeletal muscle mass and function.

Authors

Andrew C. D’Lugos, Jeremy B. Ducharme, Chandler S. Callaway, Jose G. Trevino, Carl Atkinson, Sarah M. Judge, Andrew R. Judge

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Figure 6

Deletion of C3 attenuates KPC-induced limb muscle wasting.

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Deletion of C3 attenuates KPC-induced limb muscle wasting. (A) Tibialis ...
(A) Tibialis anterior (TA) mass was reduced in KPC tumor–bearing mice (squares) versus sham (circles). (B) Deletion of complement component C3 attenuated TA muscle wasting. (C and D) Soleus (SOL) mass was reduced in KPC tumor–bearing mice (C); however, the deletion of C3 attenuated SOL wasting (D). (E) Representative images of TA cross sections stained for wheat germ agglutinin (white); scale bars: 200 μm. (F and G) Quantification of TA fiber cross-sectional area (CSA) (F) and distribution of fiber CSA (G). Data are representative of n = 8–12 mice per group. *P < 0.05, **P < 0.01, ***P < 0.001 ****P < 0.0001. (H and I) Quantitative reverse transcriptase PCR analysis of atrophy-related genes of interest involved in the ubiquitin-proteasome system (H) and the autophagy-lysosome system (I) in the TA; n = 4–6 mice per group. *P < 0.05 vs. WT sham group. †P < 0.05 vs. C3–/– KPC group. Data are presented as mean ± SEM, with individual data superimposed. Differences were assessed using a 2-way ANOVA with Šidák’s post hoc analysis (A, C, F, H, and I) and Student’s 2-tailed t test (B and D).