Cancer and chemotherapy contribute to muscle loss by activating common signaling pathways

Rafael Barreto, Giorgia Mandili, Frank Witzmann, Francesco Novelli, Teresa Zimmers, Andrea Bonetto

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Cachexia represents one of the primary complications of colorectal cancer due to its effects on depletion of muscle and fat. Evidence suggests that chemotherapeutic regimens, such as Folfiri, contribute to cachexia-related symptoms. The purpose of the present study was to investigate the cachexia signature in different conditions associated with severe muscle wasting, namely Colon-26 (C26) and Folfiri-associated cachexia. Using a quantitative LC-MS/MS approach, we identified significant changes in 386 proteins in the quadriceps muscle of Folfiri-treated mice, and 269 proteins differentially expressed in the C26 hosts (p < 0.05; -1.5 ≥ fold change ≥ +1.5). Comparative analysis isolated 240 proteins that were modulated in common, with a large majority (218) that were down-regulated in both experimental settings. Interestingly, metabolic (47.08%) and structural (21.25%) proteins were the most represented. Pathway analysis revealed mitochondrial dysfunctions in both experimental conditions, also consistent with reduced expression of mediators of mitochondrial fusion (OPA-1, mitofusin-2), fission (DRP-1) and biogenesis (Cytochrome C, PGC-1α). Alterations of oxidative phosphorylation within the TCA cycle, fatty acid metabolism, and Ca2+ signaling were also detected. Overall, the proteomic signature in the presence of both chemotherapy and cancer suggests the activation of mechanisms associated with movement disorders, necrosis, muscle cell death, muscle weakness and muscle damage. Conversely, this is consistent with the inhibition of pathways that regulate nucleotide and fatty acid metabolism, synthesis of ATP, muscle and heart function, as well as ROS scavenging. Interestingly, strong up-regulation of pro-inflammatory acute-phase proteins and a more coordinated modulation of mitochondrial and lipidic metabolisms were observed in the muscle of the C26 hosts that were different from the Folfiri-treated animals. In conclusion, our results suggest that both cancer and chemotherapy contribute to muscle loss by activating common signaling pathways. These data support the undertaking of combination strategies that aim to both counteract tumor growth and reduce chemotherapy side effects.

Original languageEnglish (US)
Article number472
JournalFrontiers in Physiology
Volume7
Issue numberOCT
DOIs
StatePublished - Oct 19 2016

Fingerprint

Cachexia
Drug Therapy
Muscles
Colon
Neoplasms
Proteins
Fatty Acids
Mitochondrial Dynamics
Acute-Phase Proteins
Oxidative Phosphorylation
Muscle Weakness
Quadriceps Muscle
Movement Disorders
Cytochromes
Proteomics
Muscle Cells
Colorectal Neoplasms
Myocardium
Cell Death
Necrosis

Keywords

  • C26
  • Cachexia
  • Folfiri
  • Inflammation
  • Mitochondria
  • Mitochondrial fusion and fission
  • Muscle
  • Proteomics

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Cancer and chemotherapy contribute to muscle loss by activating common signaling pathways. / Barreto, Rafael; Mandili, Giorgia; Witzmann, Frank; Novelli, Francesco; Zimmers, Teresa; Bonetto, Andrea.

In: Frontiers in Physiology, Vol. 7, No. OCT, 472, 19.10.2016.

Research output: Contribution to journalArticle

Barreto, Rafael ; Mandili, Giorgia ; Witzmann, Frank ; Novelli, Francesco ; Zimmers, Teresa ; Bonetto, Andrea. / Cancer and chemotherapy contribute to muscle loss by activating common signaling pathways. In: Frontiers in Physiology. 2016 ; Vol. 7, No. OCT.
@article{296e86ac47474140a9b03ea9f04c7a87,
title = "Cancer and chemotherapy contribute to muscle loss by activating common signaling pathways",
abstract = "Cachexia represents one of the primary complications of colorectal cancer due to its effects on depletion of muscle and fat. Evidence suggests that chemotherapeutic regimens, such as Folfiri, contribute to cachexia-related symptoms. The purpose of the present study was to investigate the cachexia signature in different conditions associated with severe muscle wasting, namely Colon-26 (C26) and Folfiri-associated cachexia. Using a quantitative LC-MS/MS approach, we identified significant changes in 386 proteins in the quadriceps muscle of Folfiri-treated mice, and 269 proteins differentially expressed in the C26 hosts (p < 0.05; -1.5 ≥ fold change ≥ +1.5). Comparative analysis isolated 240 proteins that were modulated in common, with a large majority (218) that were down-regulated in both experimental settings. Interestingly, metabolic (47.08{\%}) and structural (21.25{\%}) proteins were the most represented. Pathway analysis revealed mitochondrial dysfunctions in both experimental conditions, also consistent with reduced expression of mediators of mitochondrial fusion (OPA-1, mitofusin-2), fission (DRP-1) and biogenesis (Cytochrome C, PGC-1α). Alterations of oxidative phosphorylation within the TCA cycle, fatty acid metabolism, and Ca2+ signaling were also detected. Overall, the proteomic signature in the presence of both chemotherapy and cancer suggests the activation of mechanisms associated with movement disorders, necrosis, muscle cell death, muscle weakness and muscle damage. Conversely, this is consistent with the inhibition of pathways that regulate nucleotide and fatty acid metabolism, synthesis of ATP, muscle and heart function, as well as ROS scavenging. Interestingly, strong up-regulation of pro-inflammatory acute-phase proteins and a more coordinated modulation of mitochondrial and lipidic metabolisms were observed in the muscle of the C26 hosts that were different from the Folfiri-treated animals. In conclusion, our results suggest that both cancer and chemotherapy contribute to muscle loss by activating common signaling pathways. These data support the undertaking of combination strategies that aim to both counteract tumor growth and reduce chemotherapy side effects.",
keywords = "C26, Cachexia, Folfiri, Inflammation, Mitochondria, Mitochondrial fusion and fission, Muscle, Proteomics",
author = "Rafael Barreto and Giorgia Mandili and Frank Witzmann and Francesco Novelli and Teresa Zimmers and Andrea Bonetto",
year = "2016",
month = "10",
day = "19",
doi = "10.3389/fphys.2016.00472",
language = "English (US)",
volume = "7",
journal = "Frontiers in Physiology",
issn = "1664-042X",
publisher = "Frontiers Research Foundation",
number = "OCT",

}

TY - JOUR

T1 - Cancer and chemotherapy contribute to muscle loss by activating common signaling pathways

AU - Barreto, Rafael

AU - Mandili, Giorgia

AU - Witzmann, Frank

AU - Novelli, Francesco

AU - Zimmers, Teresa

AU - Bonetto, Andrea

PY - 2016/10/19

Y1 - 2016/10/19

N2 - Cachexia represents one of the primary complications of colorectal cancer due to its effects on depletion of muscle and fat. Evidence suggests that chemotherapeutic regimens, such as Folfiri, contribute to cachexia-related symptoms. The purpose of the present study was to investigate the cachexia signature in different conditions associated with severe muscle wasting, namely Colon-26 (C26) and Folfiri-associated cachexia. Using a quantitative LC-MS/MS approach, we identified significant changes in 386 proteins in the quadriceps muscle of Folfiri-treated mice, and 269 proteins differentially expressed in the C26 hosts (p < 0.05; -1.5 ≥ fold change ≥ +1.5). Comparative analysis isolated 240 proteins that were modulated in common, with a large majority (218) that were down-regulated in both experimental settings. Interestingly, metabolic (47.08%) and structural (21.25%) proteins were the most represented. Pathway analysis revealed mitochondrial dysfunctions in both experimental conditions, also consistent with reduced expression of mediators of mitochondrial fusion (OPA-1, mitofusin-2), fission (DRP-1) and biogenesis (Cytochrome C, PGC-1α). Alterations of oxidative phosphorylation within the TCA cycle, fatty acid metabolism, and Ca2+ signaling were also detected. Overall, the proteomic signature in the presence of both chemotherapy and cancer suggests the activation of mechanisms associated with movement disorders, necrosis, muscle cell death, muscle weakness and muscle damage. Conversely, this is consistent with the inhibition of pathways that regulate nucleotide and fatty acid metabolism, synthesis of ATP, muscle and heart function, as well as ROS scavenging. Interestingly, strong up-regulation of pro-inflammatory acute-phase proteins and a more coordinated modulation of mitochondrial and lipidic metabolisms were observed in the muscle of the C26 hosts that were different from the Folfiri-treated animals. In conclusion, our results suggest that both cancer and chemotherapy contribute to muscle loss by activating common signaling pathways. These data support the undertaking of combination strategies that aim to both counteract tumor growth and reduce chemotherapy side effects.

AB - Cachexia represents one of the primary complications of colorectal cancer due to its effects on depletion of muscle and fat. Evidence suggests that chemotherapeutic regimens, such as Folfiri, contribute to cachexia-related symptoms. The purpose of the present study was to investigate the cachexia signature in different conditions associated with severe muscle wasting, namely Colon-26 (C26) and Folfiri-associated cachexia. Using a quantitative LC-MS/MS approach, we identified significant changes in 386 proteins in the quadriceps muscle of Folfiri-treated mice, and 269 proteins differentially expressed in the C26 hosts (p < 0.05; -1.5 ≥ fold change ≥ +1.5). Comparative analysis isolated 240 proteins that were modulated in common, with a large majority (218) that were down-regulated in both experimental settings. Interestingly, metabolic (47.08%) and structural (21.25%) proteins were the most represented. Pathway analysis revealed mitochondrial dysfunctions in both experimental conditions, also consistent with reduced expression of mediators of mitochondrial fusion (OPA-1, mitofusin-2), fission (DRP-1) and biogenesis (Cytochrome C, PGC-1α). Alterations of oxidative phosphorylation within the TCA cycle, fatty acid metabolism, and Ca2+ signaling were also detected. Overall, the proteomic signature in the presence of both chemotherapy and cancer suggests the activation of mechanisms associated with movement disorders, necrosis, muscle cell death, muscle weakness and muscle damage. Conversely, this is consistent with the inhibition of pathways that regulate nucleotide and fatty acid metabolism, synthesis of ATP, muscle and heart function, as well as ROS scavenging. Interestingly, strong up-regulation of pro-inflammatory acute-phase proteins and a more coordinated modulation of mitochondrial and lipidic metabolisms were observed in the muscle of the C26 hosts that were different from the Folfiri-treated animals. In conclusion, our results suggest that both cancer and chemotherapy contribute to muscle loss by activating common signaling pathways. These data support the undertaking of combination strategies that aim to both counteract tumor growth and reduce chemotherapy side effects.

KW - C26

KW - Cachexia

KW - Folfiri

KW - Inflammation

KW - Mitochondria

KW - Mitochondrial fusion and fission

KW - Muscle

KW - Proteomics

UR - http://www.scopus.com/inward/record.url?scp=84995938609&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84995938609&partnerID=8YFLogxK

U2 - 10.3389/fphys.2016.00472

DO - 10.3389/fphys.2016.00472

M3 - Article

AN - SCOPUS:84995938609

VL - 7

JO - Frontiers in Physiology

JF - Frontiers in Physiology

SN - 1664-042X

IS - OCT

M1 - 472

ER -