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STAT3 activation in skeletal muscle links muscle wasting and the acute phase response in cancer cachexia.

Bonetto A, Aydogdu T, Kunzevitzky N, Guttridge DC, Khuri S, Koniaris LG, Zimmers TA - PLoS ONE (2011)

Bottom Line: 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.These results suggest that the STAT3 transcriptome is a major mechanism for 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.

View Article: PubMed Central - PubMed

Affiliation: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States of America.

ABSTRACT

Background: Cachexia, 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 findings: Moderate 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/significance: These 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.

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Expression of known genes in muscle growth regulation in C26 cachexia.A, Expression of the ubiquitin ligases, Fbxo32/Atrogin-1 and Trim63/MuRF1 are induced by microarray and qPCR analysis. Expression of genes encoding muscle structural proteins, including ACTA1 and MHY8 are decreased. B, Gene expression patterns in C26 cachexia mapped onto a schematic of muscle growth regulation pathways. Genes with demonstrated growth-promoting activity in muscle are shown in green, growth inhibitory genes in red. The number on the left represents fold-change in moderate cachexia and right in severe cachexia, with the arrow indicating the direction of the change. Genes with no values were either not changed or not present in the dataset.
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pone-0022538-g003: Expression of known genes in muscle growth regulation in C26 cachexia.A, Expression of the ubiquitin ligases, Fbxo32/Atrogin-1 and Trim63/MuRF1 are induced by microarray and qPCR analysis. Expression of genes encoding muscle structural proteins, including ACTA1 and MHY8 are decreased. B, Gene expression patterns in C26 cachexia mapped onto a schematic of muscle growth regulation pathways. Genes with demonstrated growth-promoting activity in muscle are shown in green, growth inhibitory genes in red. The number on the left represents fold-change in moderate cachexia and right in severe cachexia, with the arrow indicating the direction of the change. Genes with no values were either not changed or not present in the dataset.

Mentions: Muscle wasting of virtually all etiologies is associated with increased expression of skeletal muscle ubiquitin E3 ligases, Trim63/Murf-1 and Fbxo32/Atrogin-1 [38], [39], [40]. Both were markedly increased in our microarray analysis, with a greater increase in Trim63/Murf-1 versus Fbxo32/Atrogin-1 and higher expression in moderate versus severe wasting (Figure 3). These trends were confirmed by quantitative real-time RT-PCR. Muscle atrophy is also associated with reduced expression of RNAs encoding structural proteins. Indeed, by microarray and qRT-PCR, cardiac alpha actin and myosin heavy chain 8 were down regulated, more so in severe versus moderate wasting. These results are consistent with reports from others in C26 cachexia [33].


STAT3 activation in skeletal muscle links muscle wasting and the acute phase response in cancer cachexia.

Bonetto A, Aydogdu T, Kunzevitzky N, Guttridge DC, Khuri S, Koniaris LG, Zimmers TA - PLoS ONE (2011)

Expression of known genes in muscle growth regulation in C26 cachexia.A, Expression of the ubiquitin ligases, Fbxo32/Atrogin-1 and Trim63/MuRF1 are induced by microarray and qPCR analysis. Expression of genes encoding muscle structural proteins, including ACTA1 and MHY8 are decreased. B, Gene expression patterns in C26 cachexia mapped onto a schematic of muscle growth regulation pathways. Genes with demonstrated growth-promoting activity in muscle are shown in green, growth inhibitory genes in red. The number on the left represents fold-change in moderate cachexia and right in severe cachexia, with the arrow indicating the direction of the change. Genes with no values were either not changed or not present in the dataset.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3140523&req=5

pone-0022538-g003: Expression of known genes in muscle growth regulation in C26 cachexia.A, Expression of the ubiquitin ligases, Fbxo32/Atrogin-1 and Trim63/MuRF1 are induced by microarray and qPCR analysis. Expression of genes encoding muscle structural proteins, including ACTA1 and MHY8 are decreased. B, Gene expression patterns in C26 cachexia mapped onto a schematic of muscle growth regulation pathways. Genes with demonstrated growth-promoting activity in muscle are shown in green, growth inhibitory genes in red. The number on the left represents fold-change in moderate cachexia and right in severe cachexia, with the arrow indicating the direction of the change. Genes with no values were either not changed or not present in the dataset.
Mentions: Muscle wasting of virtually all etiologies is associated with increased expression of skeletal muscle ubiquitin E3 ligases, Trim63/Murf-1 and Fbxo32/Atrogin-1 [38], [39], [40]. Both were markedly increased in our microarray analysis, with a greater increase in Trim63/Murf-1 versus Fbxo32/Atrogin-1 and higher expression in moderate versus severe wasting (Figure 3). These trends were confirmed by quantitative real-time RT-PCR. Muscle atrophy is also associated with reduced expression of RNAs encoding structural proteins. Indeed, by microarray and qRT-PCR, cardiac alpha actin and myosin heavy chain 8 were down regulated, more so in severe versus moderate wasting. These results are consistent with reports from others in C26 cachexia [33].

Bottom Line: 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.These results suggest that the STAT3 transcriptome is a major mechanism for 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.

View Article: PubMed Central - PubMed

Affiliation: Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, United States of America.

ABSTRACT

Background: Cachexia, 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 findings: Moderate 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/significance: These 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.

Show MeSH
Related in: MedlinePlus