Acute inhibition of myostatin-family proteins preserves skeletal muscle in mouse models of cancer cachexia

Margaret E. Benny Klimek, Tufan Aydogdu, Majik J. Link, Marianne Pons, Leonidas Koniaris, Teresa Zimmers

Research output: Contribution to journalArticle

123 Citations (Scopus)

Abstract

Cachexia, progressive loss of fat and muscle mass despite adequate nutrition, is a devastating complication of cancer associated with poor quality of life and increased mortality. Myostatin is a potent tonic muscle growth inhibitor. We tested how myostatin inhibition might influence cancer cachexia using genetic and pharmacological approaches. First, hypermuscular myostatin null mice were injected with Lewis lung carcinoma or B16F10 melanoma cells. Myostatin null mice were more sensitive to tumor-induced cachexia, losing more absolute mass and proportionately more muscle mass than wild-type mice. Because myostatin null mice lack expression from development, however, we also sought to manipulate myostatin acutely. The histone deacetylase inhibitor Trichostatin A has been shown to increase muscle mass in normal and dystrophic mice by inducing the myostatin inhibitor, follistatin. Although Trichostatin A administration induced muscle growth in normal mice, it failed to preserve muscle in colon-26 cancer cachexia. Finally we sought to inhibit myostatin and related ligands by administration of the Activin receptor extracellular domain/Fc fusion protein, ACVR2B-Fc. Systemic administration of ACVR2B-Fc potently inhibited muscle wasting and protected adipose stores in both colon-26 and Lewis lung carcinoma cachexia, without affecting tumor growth. Enhanced cachexia in myostatin knockouts indicates that host-derived myostatin is not the sole mediator of muscle wasting in cancer. More importantly, skeletal muscle preservation with ACVR2B-Fc establishes that targeting myostatin-family ligands using ACVR2B-Fc or related molecules is an important and potent therapeutic avenue in cancer cachexia.

Original languageEnglish (US)
Pages (from-to)1548-1554
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume391
Issue number3
DOIs
StatePublished - Jan 15 2010
Externally publishedYes

Fingerprint

Myostatin
Cachexia
Muscle
Skeletal Muscle
Muscles
Neoplasms
Proteins
trichostatin A
Lewis Lung Carcinoma
Tumors
Activin Receptors
Follistatin
Ligands
Growth Inhibitors
Histone Deacetylase Inhibitors
Nutrition
Growth
Colonic Neoplasms
Melanoma
Colon

Keywords

  • ACVR2B
  • Cachexia
  • Cancer
  • Myostatin
  • Skeletal muscle atrophy
  • Trichostatin

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Cell Biology
  • Molecular Biology

Cite this

Acute inhibition of myostatin-family proteins preserves skeletal muscle in mouse models of cancer cachexia. / Benny Klimek, Margaret E.; Aydogdu, Tufan; Link, Majik J.; Pons, Marianne; Koniaris, Leonidas; Zimmers, Teresa.

In: Biochemical and Biophysical Research Communications, Vol. 391, No. 3, 15.01.2010, p. 1548-1554.

Research output: Contribution to journalArticle

@article{0ee866b2c48c4e7ebeb2ced1c5796e2f,
title = "Acute inhibition of myostatin-family proteins preserves skeletal muscle in mouse models of cancer cachexia",
abstract = "Cachexia, progressive loss of fat and muscle mass despite adequate nutrition, is a devastating complication of cancer associated with poor quality of life and increased mortality. Myostatin is a potent tonic muscle growth inhibitor. We tested how myostatin inhibition might influence cancer cachexia using genetic and pharmacological approaches. First, hypermuscular myostatin null mice were injected with Lewis lung carcinoma or B16F10 melanoma cells. Myostatin null mice were more sensitive to tumor-induced cachexia, losing more absolute mass and proportionately more muscle mass than wild-type mice. Because myostatin null mice lack expression from development, however, we also sought to manipulate myostatin acutely. The histone deacetylase inhibitor Trichostatin A has been shown to increase muscle mass in normal and dystrophic mice by inducing the myostatin inhibitor, follistatin. Although Trichostatin A administration induced muscle growth in normal mice, it failed to preserve muscle in colon-26 cancer cachexia. Finally we sought to inhibit myostatin and related ligands by administration of the Activin receptor extracellular domain/Fc fusion protein, ACVR2B-Fc. Systemic administration of ACVR2B-Fc potently inhibited muscle wasting and protected adipose stores in both colon-26 and Lewis lung carcinoma cachexia, without affecting tumor growth. Enhanced cachexia in myostatin knockouts indicates that host-derived myostatin is not the sole mediator of muscle wasting in cancer. More importantly, skeletal muscle preservation with ACVR2B-Fc establishes that targeting myostatin-family ligands using ACVR2B-Fc or related molecules is an important and potent therapeutic avenue in cancer cachexia.",
keywords = "ACVR2B, Cachexia, Cancer, Myostatin, Skeletal muscle atrophy, Trichostatin",
author = "{Benny Klimek}, {Margaret E.} and Tufan Aydogdu and Link, {Majik J.} and Marianne Pons and Leonidas Koniaris and Teresa Zimmers",
year = "2010",
month = "1",
day = "15",
doi = "10.1016/j.bbrc.2009.12.123",
language = "English (US)",
volume = "391",
pages = "1548--1554",
journal = "Biochemical and Biophysical Research Communications",
issn = "0006-291X",
publisher = "Academic Press Inc.",
number = "3",

}

TY - JOUR

T1 - Acute inhibition of myostatin-family proteins preserves skeletal muscle in mouse models of cancer cachexia

AU - Benny Klimek, Margaret E.

AU - Aydogdu, Tufan

AU - Link, Majik J.

AU - Pons, Marianne

AU - Koniaris, Leonidas

AU - Zimmers, Teresa

PY - 2010/1/15

Y1 - 2010/1/15

N2 - Cachexia, progressive loss of fat and muscle mass despite adequate nutrition, is a devastating complication of cancer associated with poor quality of life and increased mortality. Myostatin is a potent tonic muscle growth inhibitor. We tested how myostatin inhibition might influence cancer cachexia using genetic and pharmacological approaches. First, hypermuscular myostatin null mice were injected with Lewis lung carcinoma or B16F10 melanoma cells. Myostatin null mice were more sensitive to tumor-induced cachexia, losing more absolute mass and proportionately more muscle mass than wild-type mice. Because myostatin null mice lack expression from development, however, we also sought to manipulate myostatin acutely. The histone deacetylase inhibitor Trichostatin A has been shown to increase muscle mass in normal and dystrophic mice by inducing the myostatin inhibitor, follistatin. Although Trichostatin A administration induced muscle growth in normal mice, it failed to preserve muscle in colon-26 cancer cachexia. Finally we sought to inhibit myostatin and related ligands by administration of the Activin receptor extracellular domain/Fc fusion protein, ACVR2B-Fc. Systemic administration of ACVR2B-Fc potently inhibited muscle wasting and protected adipose stores in both colon-26 and Lewis lung carcinoma cachexia, without affecting tumor growth. Enhanced cachexia in myostatin knockouts indicates that host-derived myostatin is not the sole mediator of muscle wasting in cancer. More importantly, skeletal muscle preservation with ACVR2B-Fc establishes that targeting myostatin-family ligands using ACVR2B-Fc or related molecules is an important and potent therapeutic avenue in cancer cachexia.

AB - Cachexia, progressive loss of fat and muscle mass despite adequate nutrition, is a devastating complication of cancer associated with poor quality of life and increased mortality. Myostatin is a potent tonic muscle growth inhibitor. We tested how myostatin inhibition might influence cancer cachexia using genetic and pharmacological approaches. First, hypermuscular myostatin null mice were injected with Lewis lung carcinoma or B16F10 melanoma cells. Myostatin null mice were more sensitive to tumor-induced cachexia, losing more absolute mass and proportionately more muscle mass than wild-type mice. Because myostatin null mice lack expression from development, however, we also sought to manipulate myostatin acutely. The histone deacetylase inhibitor Trichostatin A has been shown to increase muscle mass in normal and dystrophic mice by inducing the myostatin inhibitor, follistatin. Although Trichostatin A administration induced muscle growth in normal mice, it failed to preserve muscle in colon-26 cancer cachexia. Finally we sought to inhibit myostatin and related ligands by administration of the Activin receptor extracellular domain/Fc fusion protein, ACVR2B-Fc. Systemic administration of ACVR2B-Fc potently inhibited muscle wasting and protected adipose stores in both colon-26 and Lewis lung carcinoma cachexia, without affecting tumor growth. Enhanced cachexia in myostatin knockouts indicates that host-derived myostatin is not the sole mediator of muscle wasting in cancer. More importantly, skeletal muscle preservation with ACVR2B-Fc establishes that targeting myostatin-family ligands using ACVR2B-Fc or related molecules is an important and potent therapeutic avenue in cancer cachexia.

KW - ACVR2B

KW - Cachexia

KW - Cancer

KW - Myostatin

KW - Skeletal muscle atrophy

KW - Trichostatin

UR - http://www.scopus.com/inward/record.url?scp=73949143033&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=73949143033&partnerID=8YFLogxK

U2 - 10.1016/j.bbrc.2009.12.123

DO - 10.1016/j.bbrc.2009.12.123

M3 - Article

VL - 391

SP - 1548

EP - 1554

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

SN - 0006-291X

IS - 3

ER -