Myostatin Neutralization Results in Preservation of Muscle Mass and Strength in Preclinical Models of Tumor-Induced Muscle Wasting

• Published in: Molecular cancer therapeutics Vol. 14; no. 7; pp. 1661 - 1670
• Main Authors: Smith, Rosamund C., Cramer, Martin S., Mitchell, Pamela J., Capen, Andrew, Huber, Lysiane, Wang, Rong, Myers, Laura, Jones, Bryan E., Eastwood, Brian J., Ballard, Darryl, Hanson, Jeff, Credille, Kelly M., Wroblewski, Victor J., Lin, Boris K., Heuer, Josef G.
• Format: Journal Article
• Language: English
• Published: United States 01.07.2015
• Subjects: Animals; Antibodies, Neutralizing - immunology; Antibodies, Neutralizing - pharmacology; Antibody Affinity - immunology; Body Weight - drug effects; Cell Line, Tumor; Drug Evaluation, Preclinical; Female; HEK293 Cells; Humans; Male; Mice, Inbred BALB C; Mice, SCID; Muscle Strength - drug effects; Muscle, Skeletal - drug effects; Muscle, Skeletal - pathology; Muscle, Skeletal - physiopathology; Myofibrils - drug effects; Myostatin - immunology; Neoplasms - complications; Neoplasms - drug therapy; Neoplasms, Experimental - complications; Neoplasms, Experimental - drug therapy; Transplantation, Heterologous; Treatment Outcome; Wasting Syndrome - drug therapy; Wasting Syndrome - etiology
• DOI: 10.1158/1535-7163.MCT-14-0681
• ISSN: 1535-7163

Skeletal muscle wasting occurs in a great majority of cancer patients with advanced disease and is associated with a poor prognosis and decreased survival. Myostatin functions as a negative regulator of skeletal muscle mass and has recently become a therapeutic target for reducing the loss of skeletal muscle and strength associated with clinical myopathies. We generated neutralizing antibodies to myostatin to test their potential use as therapeutic agents to attenuate the skeletal muscle wasting due to cancer. We show that our neutralizing antimyostatin antibodies significantly increase body weight, skeletal muscle mass, and strength in non–tumor-bearing mice with a concomitant increase in mean myofiber area. The administration of these neutralizing antibodies in two preclinical models of cancer-induced muscle wasting (C26 colon adenocarcinoma and PC3 prostate carcinoma) resulted in a significant attenuation of the loss of muscle mass and strength with no effect on tumor growth. We also show that the skeletal muscle mass– and strength-preserving effect of the antibodies is not affected by the coadministration of gemcitabine, a common chemotherapeutic agent, in both non–tumor-bearing mice and mice bearing C26 tumors. In addition, we show that myostatin neutralization with these antibodies results in the preservation of skeletal muscle mass following reduced caloric intake, a common comorbidity associated with advanced cancer. Our findings support the use of neutralizing antimyostatin antibodies as potential therapeutics for cancer-induced muscle wasting. Mol Cancer Ther; 14(7); 1661–70. ©2015 AACR.