Activin-{beta}C modulates cachexia by repressing the ubiquitin-proteasome and autophagic degradation pathways

Francesco E Marino, Gail P Risbridger, Elspeth J Gold

Research output: Contribution to journalArticleResearchpeer-review

14 Citations (Scopus)

Abstract

BACKGROUND: Cancer-associated cachexia and muscle wasting are considered key determinants of cancer-related death and reduction in the quality of life of cancer patients. A crucial link has been established between activin signaling and skeletal muscle atrophy-hypertrophy. We previously showed that activin-?C, a novel activin-A antagonist, is a tumor modulator that abolishes the cancer-associated cachexia in a mouse genetic model of gonadal tumorigenesis, in which the normal balance of inhibin/activin signalling is disrupted by a targeted mutation in the Inha gene (inhibin a-KO mouse). This study aimed to identify the molecular mechanism by which activin-?C increases survival and abolishes cancer-associated cachexia in a-KO mice. We hypothesized that overexpression of activin-?C modulates the cachexia phenotype by antagonizing the activin signaling pathway and repressing muscle wasting via the ubiquitin-proteasome and the autophagic-lysosomal degradation pathways. METHODS: Male and female ActC++, a-KO, and a-KO/ActC++ mice and WT littermate controls were studied. Western blot analysis for the specific E3 ubiquitin ligases, atrogin-1 and MuRF1, markers of the autophagic-lysosomal pathway, Beclin-1, p62, and LC3A/B, effectors Smad-2, Smad-3 and myostatin was performed in the gastrocnemius of age-matched mice. Histopathology of the gastrocnemius and survival analysis were also conducted in animals from the same breeding cohort. Serum levels of activin-A, inflammatory cytokines, hormonal profile, and bone density were also assessed. RESULTS: Increased levels of atrogin-1, MuRF-1, Beclin-1, p62, LC3A/B-I, Smad-2 and serum levels of activin-A were noted in the a-KO mice. These mice developed gonadal cancers followed by severe weight loss, and reduced survival. Overexpression of activin- ?C antagonized the activin signaling cascade, attenuating the ubiquitin-proteasome and the autophagic-lysosomal degradation pathways, and reduced serum levels of activin-A. a-KO/ActC++ mice displayed a less aggressive cachectic phenotype, reduced tumor weight, and prolonged survival. CONCLUSION: Our findings show for the first time a specific effect of activin-?C on muscle wasting and transcription factors involved in muscle protein degradation. The study indicates that activin-?C may be a novel therapy to abrogate cancer-associated weight loss and prolong survival.
Original languageEnglish
Pages (from-to)365 - 380
Number of pages16
JournalJournal of Cachexia, Sarcopenia and Muscle
Volume6
Issue number4
DOIs
Publication statusPublished - 2015

Cite this

@article{ccd40efc9b86407bbd2f7a2d02d0f64b,
title = "Activin-{beta}C modulates cachexia by repressing the ubiquitin-proteasome and autophagic degradation pathways",
abstract = "BACKGROUND: Cancer-associated cachexia and muscle wasting are considered key determinants of cancer-related death and reduction in the quality of life of cancer patients. A crucial link has been established between activin signaling and skeletal muscle atrophy-hypertrophy. We previously showed that activin-?C, a novel activin-A antagonist, is a tumor modulator that abolishes the cancer-associated cachexia in a mouse genetic model of gonadal tumorigenesis, in which the normal balance of inhibin/activin signalling is disrupted by a targeted mutation in the Inha gene (inhibin a-KO mouse). This study aimed to identify the molecular mechanism by which activin-?C increases survival and abolishes cancer-associated cachexia in a-KO mice. We hypothesized that overexpression of activin-?C modulates the cachexia phenotype by antagonizing the activin signaling pathway and repressing muscle wasting via the ubiquitin-proteasome and the autophagic-lysosomal degradation pathways. METHODS: Male and female ActC++, a-KO, and a-KO/ActC++ mice and WT littermate controls were studied. Western blot analysis for the specific E3 ubiquitin ligases, atrogin-1 and MuRF1, markers of the autophagic-lysosomal pathway, Beclin-1, p62, and LC3A/B, effectors Smad-2, Smad-3 and myostatin was performed in the gastrocnemius of age-matched mice. Histopathology of the gastrocnemius and survival analysis were also conducted in animals from the same breeding cohort. Serum levels of activin-A, inflammatory cytokines, hormonal profile, and bone density were also assessed. RESULTS: Increased levels of atrogin-1, MuRF-1, Beclin-1, p62, LC3A/B-I, Smad-2 and serum levels of activin-A were noted in the a-KO mice. These mice developed gonadal cancers followed by severe weight loss, and reduced survival. Overexpression of activin- ?C antagonized the activin signaling cascade, attenuating the ubiquitin-proteasome and the autophagic-lysosomal degradation pathways, and reduced serum levels of activin-A. a-KO/ActC++ mice displayed a less aggressive cachectic phenotype, reduced tumor weight, and prolonged survival. CONCLUSION: Our findings show for the first time a specific effect of activin-?C on muscle wasting and transcription factors involved in muscle protein degradation. The study indicates that activin-?C may be a novel therapy to abrogate cancer-associated weight loss and prolong survival.",
author = "Marino, {Francesco E} and Risbridger, {Gail P} and Gold, {Elspeth J}",
year = "2015",
doi = "10.1002/jcsm.12031",
language = "English",
volume = "6",
pages = "365 -- 380",
journal = "Journal of Cachexia, Sarcopenia and Muscle",
issn = "2190-5991",
publisher = "Wiley-Blackwell",
number = "4",

}

Activin-{beta}C modulates cachexia by repressing the ubiquitin-proteasome and autophagic degradation pathways. / Marino, Francesco E; Risbridger, Gail P; Gold, Elspeth J.

In: Journal of Cachexia, Sarcopenia and Muscle, Vol. 6, No. 4, 2015, p. 365 - 380.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Activin-{beta}C modulates cachexia by repressing the ubiquitin-proteasome and autophagic degradation pathways

AU - Marino, Francesco E

AU - Risbridger, Gail P

AU - Gold, Elspeth J

PY - 2015

Y1 - 2015

N2 - BACKGROUND: Cancer-associated cachexia and muscle wasting are considered key determinants of cancer-related death and reduction in the quality of life of cancer patients. A crucial link has been established between activin signaling and skeletal muscle atrophy-hypertrophy. We previously showed that activin-?C, a novel activin-A antagonist, is a tumor modulator that abolishes the cancer-associated cachexia in a mouse genetic model of gonadal tumorigenesis, in which the normal balance of inhibin/activin signalling is disrupted by a targeted mutation in the Inha gene (inhibin a-KO mouse). This study aimed to identify the molecular mechanism by which activin-?C increases survival and abolishes cancer-associated cachexia in a-KO mice. We hypothesized that overexpression of activin-?C modulates the cachexia phenotype by antagonizing the activin signaling pathway and repressing muscle wasting via the ubiquitin-proteasome and the autophagic-lysosomal degradation pathways. METHODS: Male and female ActC++, a-KO, and a-KO/ActC++ mice and WT littermate controls were studied. Western blot analysis for the specific E3 ubiquitin ligases, atrogin-1 and MuRF1, markers of the autophagic-lysosomal pathway, Beclin-1, p62, and LC3A/B, effectors Smad-2, Smad-3 and myostatin was performed in the gastrocnemius of age-matched mice. Histopathology of the gastrocnemius and survival analysis were also conducted in animals from the same breeding cohort. Serum levels of activin-A, inflammatory cytokines, hormonal profile, and bone density were also assessed. RESULTS: Increased levels of atrogin-1, MuRF-1, Beclin-1, p62, LC3A/B-I, Smad-2 and serum levels of activin-A were noted in the a-KO mice. These mice developed gonadal cancers followed by severe weight loss, and reduced survival. Overexpression of activin- ?C antagonized the activin signaling cascade, attenuating the ubiquitin-proteasome and the autophagic-lysosomal degradation pathways, and reduced serum levels of activin-A. a-KO/ActC++ mice displayed a less aggressive cachectic phenotype, reduced tumor weight, and prolonged survival. CONCLUSION: Our findings show for the first time a specific effect of activin-?C on muscle wasting and transcription factors involved in muscle protein degradation. The study indicates that activin-?C may be a novel therapy to abrogate cancer-associated weight loss and prolong survival.

AB - BACKGROUND: Cancer-associated cachexia and muscle wasting are considered key determinants of cancer-related death and reduction in the quality of life of cancer patients. A crucial link has been established between activin signaling and skeletal muscle atrophy-hypertrophy. We previously showed that activin-?C, a novel activin-A antagonist, is a tumor modulator that abolishes the cancer-associated cachexia in a mouse genetic model of gonadal tumorigenesis, in which the normal balance of inhibin/activin signalling is disrupted by a targeted mutation in the Inha gene (inhibin a-KO mouse). This study aimed to identify the molecular mechanism by which activin-?C increases survival and abolishes cancer-associated cachexia in a-KO mice. We hypothesized that overexpression of activin-?C modulates the cachexia phenotype by antagonizing the activin signaling pathway and repressing muscle wasting via the ubiquitin-proteasome and the autophagic-lysosomal degradation pathways. METHODS: Male and female ActC++, a-KO, and a-KO/ActC++ mice and WT littermate controls were studied. Western blot analysis for the specific E3 ubiquitin ligases, atrogin-1 and MuRF1, markers of the autophagic-lysosomal pathway, Beclin-1, p62, and LC3A/B, effectors Smad-2, Smad-3 and myostatin was performed in the gastrocnemius of age-matched mice. Histopathology of the gastrocnemius and survival analysis were also conducted in animals from the same breeding cohort. Serum levels of activin-A, inflammatory cytokines, hormonal profile, and bone density were also assessed. RESULTS: Increased levels of atrogin-1, MuRF-1, Beclin-1, p62, LC3A/B-I, Smad-2 and serum levels of activin-A were noted in the a-KO mice. These mice developed gonadal cancers followed by severe weight loss, and reduced survival. Overexpression of activin- ?C antagonized the activin signaling cascade, attenuating the ubiquitin-proteasome and the autophagic-lysosomal degradation pathways, and reduced serum levels of activin-A. a-KO/ActC++ mice displayed a less aggressive cachectic phenotype, reduced tumor weight, and prolonged survival. CONCLUSION: Our findings show for the first time a specific effect of activin-?C on muscle wasting and transcription factors involved in muscle protein degradation. The study indicates that activin-?C may be a novel therapy to abrogate cancer-associated weight loss and prolong survival.

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U2 - 10.1002/jcsm.12031

DO - 10.1002/jcsm.12031

M3 - Article

VL - 6

SP - 365

EP - 380

JO - Journal of Cachexia, Sarcopenia and Muscle

JF - Journal of Cachexia, Sarcopenia and Muscle

SN - 2190-5991

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ER -