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 7

Deletion of C3 ameliorates KPC-induced diaphragm atrophy and fibrosis.

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Deletion of C3 ameliorates KPC-induced diaphragm atrophy and fibrosis. (...
(A) Representative images of costal diaphragm cross sections from sham and KPC tumor–bearing mice stained for MyHC I (red), MyHC IIa (blue), and wheat germ agglutinin (green); scale bars: 100 μm. (B–E) Fiber type–specific muscle fiber size, quantified as minimum Feret’s diameter (MFD), was determined for MyHC I fibers (B), MyHC I/IIa hybrid fibers (C), MyHC IIa fibers (D), and MyHC IIx/IIb (unstained) fibers (E). (F–I) Relative abundance of MyHC I (F), MyHC I/IIa hybrid (G), MyHC IIa (H), and MyHC IIx/IIb fibers (I). Data are presented as mean ± SEM, with individual data superimposed. Data are representative of n = 4–12 mice per group. Differences were assessed using a 2-way ANOVA with Šidák’s post hoc analysis. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.