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 9

Deletion of C3 preserves in vivo and ex vivo diaphragm function during KPC tumor burden.

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Deletion of C3 preserves in vivo and ex vivo diaphragm function during K...
(A) Representative M-mode ultrasonography traces of in vivo diaphragm contractions at day 14 after surgery in sham and KPC tumor–bearing mice. (B–D) M-mode ultrasonography was used to quantify diaphragm excursion (B), respiratory rate (C), and minute ventilation (D). (E) Representative tetanic force traces recorded from costal diaphragm of WT and C3–/– KPC tumor–bearing mice. (F) Maximal normalized tetanic force recorded from costal diaphragm of WT and C3–/– KPC tumor–bearing mice. (G) Force-frequency analysis of costal diaphragm demonstrated lower normalized force production in WT mice across a range of stimulation frequencies. Data are presented as mean ± SEM, with individual data superimposed. Data are representative of n = 4–9 mice per group. Differences were assessed using a 2-way ANOVA with Šidák’s post hoc analysis (B–D and G) and Student’s 2-tailed t test (F). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.