STAT3 Activation in Skeletal Muscle Links Muscle Wasting and the Acute Phase Response in Cancer Cachexia

Andrea Bonetto,Teresa A Zimmers,Sawsan Khuri,Tufan Aydogdu,Noelia Kunzevitzky,Leonidas G Koniaris,Denis C Guttridge,Gianni Parise

doi:10.1371/journal.pone.0022538

Andrea Bonetto, Teresa A Zimmers + Show 6 more

Open Access

https://doi.org/10.1371/journal.pone.0022538

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Abstract

BackgroundCachexia, or weight loss despite adequate nutrition, significantly impairs quality of life and response to therapy in cancer patients. In cancer patients, skeletal muscle wasting, weight loss and mortality are all positively associated with increased serum cytokines, particularly Interleukin-6 (IL-6), and the presence of the acute phase response. Acute phase proteins, including fibrinogen and serum amyloid A (SAA) are synthesized by hepatocytes in response to IL-6 as part of the innate immune response. To gain insight into the relationships among these observations, we studied mice with moderate and severe Colon-26 (C26)-carcinoma cachexia.Methodology/Principal FindingsModerate and severe C26 cachexia was associated with high serum IL-6 and IL-6 family cytokines and highly similar patterns of skeletal muscle gene expression. The top canonical pathways up-regulated in both were the complement/coagulation cascade, proteasome, MAPK signaling, and the IL-6 and STAT3 pathways. Cachexia was associated with increased muscle pY705-STAT3 and increased STAT3 localization in myonuclei. STAT3 target genes, including SOCS3 mRNA and acute phase response proteins, were highly induced in cachectic muscle. IL-6 treatment and STAT3 activation both also induced fibrinogen in cultured C2C12 myotubes. Quantitation of muscle versus liver fibrinogen and SAA protein levels indicates that muscle contributes a large fraction of serum acute phase proteins in cancer.Conclusions/SignificanceThese results suggest that the STAT3 transcriptome is a major mechanism for wasting in cancer. Through IL-6/STAT3 activation, skeletal muscle is induced to synthesize acute phase proteins, thus establishing a molecular link between the observations of high IL-6, increased acute phase response proteins and muscle wasting in cancer. These results suggest a mechanism by which STAT3 might causally influence muscle wasting by altering the profile of genes expressed and translated in muscle such that amino acids liberated by increased proteolysis in cachexia are synthesized into acute phase proteins and exported into the blood.

Highlights

Cachexia, or progressive wasting of fat and skeletal muscle despite adequate nutrition, is a pervasive and devastating complication of cancer [1,2,3]
As in most cancer patients, food intake is not reduced in C26 cachexia and IL-6 levels are elevated [30]
We chose C26 adenocarcinoma, which exhibits increased circulating levels of IL-6 that coincide with muscle wasting [15]

Summary

Introduction

Progressive wasting of fat and skeletal muscle despite adequate nutrition, is a pervasive and devastating complication of cancer [1,2,3]. Cancer cachexia is defined as weight loss of at least 5% in the presence of underlying illness with associated muscle weakness, fatigue, anorexia, low lean body mass and abnormal biochemistry, including increased inflammation, anemia and low serum albumin. Weight loss despite adequate nutrition, significantly impairs quality of life and response to therapy in cancer patients. Skeletal muscle wasting, weight loss and mortality are all positively associated with increased serum cytokines, Interleukin-6 (IL-6), and the presence of the acute phase response. To gain insight into the relationships among these observations, we studied mice with moderate and severe Colon-26 (C26)-carcinoma cachexia

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