Antibody-directed myostatin inhibition enhances muscle mass and function in tumor-bearing mice

Abstract

Cancer cachexia describes the progressive skeletal muscle wasting and weakness in many cancer patients and accounts for >20% of cancer-related deaths. We tested the hypothesis that antibody-directed myostatin inhibition would attenuate the atrophy and loss of function in muscles of tumor-bearing mice. Twelve-week-old C57BL/6 mice received a subcutaneous injection of saline (control) or Lewis lung carcinoma (LLC) tumor cells. One week later, mice received either once weekly injections of saline (control, n = 12; LLC, n = 9) or a mouse chimera of anti-human myostatin antibody (PF-354, 10 mg·kg⁻¹·wk⁻¹, LLC+PF-354, n = 11) for 5 wk. Injection of LLC cells reduced muscle mass and maximum force of tibialis anterior (TA) muscles by 8-10% (P < 0.05), but the muscle atrophy and weakness were prevented with PF-354 treatment (P > 0.05). Maximum specific (normalized) force of diaphragm muscle strips was reduced with LLC injection (P < 0.05) but was not improved with PF-354 treatment (P > 0.05). PF-354 enhanced activity of oxidative enzymes in TA and diaphragm muscles of tumor-bearing mice by 118% and 89%, respectively (P < 0.05). Compared with controls, apoptosis that was not of myofibrillar or satellite cell origin was 140% higher in TA muscle cross sections from saline-treated LLC tumor-bearing mice (P < 0.05) but was not different in PF-354-treated tumor-bearing mice (P > 0.05). Antibody-directed myostatin inhibition attenuated the skeletal muscle atrophy and loss of muscle force-producing capacity in a murine model of cancer cachexia, in part by reducing apoptosis. The improvements in limb muscle mass and function highlight the therapeutic potential of antibody-directed myostatin inhibition for cancer cachexia.

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

“…This is important as the loss of muscle strength in cancer cachexia patients is known to significantly contribute not only to the morbidity and mortality of the condition, but also to the quality of life for these patients (28). Our data are also consistent with results from a recent study in which a myostatin antibody was shown to prevent the loss of muscle mass and strength in a Lewis Lung carcinoma tumor model (16).…”

“…In addition, antisense RNA administration has resulted in less skeletal muscle loss in a preclinical model of cancer cachexia (12). Although antibody-mediated myostatin inhibition has been shown to reduce skeletal muscle loss in several noncancer preclinical models of muscle wasting (13)(14)(15), only one previous report describes inhibition in a model of cancer cachexia (16). We report here the preclinical characterization of LSN2478185, a myostatin neutralizing mouse IgG1 monoclonal antibody and its derivative LY2495655, a humanized neutralizing monoclonal antibody to myostatin that can significantly attenuate loss of skeletal muscle mass and function associated with tumor burden.…”

Physiological characterization of a mouse model of cachexia in colorectal liver metastases

“…TA muscles were mounted in an embedding medium and frozen in thawing isopentane for later histochemical and biochemical analyses. The TA muscle was chosen because 1) it is of sufficient mass and cross-sectional area (CSA) for conducting these analyses, 2) we have found that it is susceptible to atrophy and functional impairment in the C-26 (24) and LLC tumor-bearing models (23), and 3) we have previously investigated histochemical and biochemical properties of this muscle in the C-26 (24) and LLC tumor-bearing models (23). Although it would be of interest to also examine histochemical and biochemical properties in muscles predominantly composed of type I fibers, such as in the soleus muscle, the small mass of the soleus (5-6 mg) precludes its use in these analyses.…”

Cancer cachexia, mechanism and treatment

“…It has been suggested that eicosanoids also mediate inflammation in cancer cachexia [38][39][40] . There is considerable evidence that signaling through cytokines and myostatin/activin pathways has a role in cancer cachexia and anorexia [41][42][43] ( Figure 1). Numerous cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), IL-6, and interferon-gamma (IFN-γ), have been postulated to play a role in the etiology of cancer cachexia [44][45][46][47][48][49][50][51][52] .…”