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Acute inhibition of myostatin-family proteins preserves skeletal muscle in mouse models of cancer cachexia.
Biochem Biophys Res Commun. 2010 Jan 15; 391(3):1548-54.BB

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.

Authors+Show Affiliations

Department of Cell Biology & Anatomy, University of Miami Miller School of Medicine, Miami, FL 33136, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

20036643

Citation

Benny Klimek, Margaret E., et al. "Acute Inhibition of Myostatin-family Proteins Preserves Skeletal Muscle in Mouse Models of Cancer Cachexia." Biochemical and Biophysical Research Communications, vol. 391, no. 3, 2010, pp. 1548-54.
Benny Klimek ME, Aydogdu T, Link MJ, et al. Acute inhibition of myostatin-family proteins preserves skeletal muscle in mouse models of cancer cachexia. Biochem Biophys Res Commun. 2010;391(3):1548-54.
Benny Klimek, M. E., Aydogdu, T., Link, M. J., Pons, M., Koniaris, L. G., & Zimmers, T. A. (2010). Acute inhibition of myostatin-family proteins preserves skeletal muscle in mouse models of cancer cachexia. Biochemical and Biophysical Research Communications, 391(3), 1548-54. https://doi.org/10.1016/j.bbrc.2009.12.123
Benny Klimek ME, et al. Acute Inhibition of Myostatin-family Proteins Preserves Skeletal Muscle in Mouse Models of Cancer Cachexia. Biochem Biophys Res Commun. 2010 Jan 15;391(3):1548-54. PubMed PMID: 20036643.
* Article titles in AMA citation format should be in sentence-case
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 G, AU - Zimmers,Teresa A, Y1 - 2009/12/28/ PY - 2009/12/03/received PY - 2009/12/21/accepted PY - 2009/12/29/entrez PY - 2009/12/29/pubmed PY - 2010/2/23/medline SP - 1548 EP - 54 JF - Biochemical and biophysical research communications JO - Biochem. Biophys. Res. Commun. VL - 391 IS - 3 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. SN - 1090-2104 UR - https://www.unboundmedicine.com/medline/citation/20036643/Acute_inhibition_of_myostatin_family_proteins_preserves_skeletal_muscle_in_mouse_models_of_cancer_cachexia_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-291X(09)02496-6 DB - PRIME DP - Unbound Medicine ER -