title: 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.
authors.affiliation: Basic and Clinical Myology Laboratory, Department of Physiology, The University of Melbourne, Victoria, Australia.
authors.forename: Kate T
authors.initials: KT
authors.lastname: Murphy
authors.forename: Annabel
authors.initials: A
authors.lastname: Chee
authors.forename: Ben G
authors.initials: BG
authors.lastname: Gleeson
authors.forename: Timur
authors.initials: T
authors.lastname: Naim
authors.forename: Kristy
authors.initials: K
authors.lastname: Swiderski
authors.forename: René
authors.initials: R
authors.lastname: Koopman
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Lynch
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002100:Cachexia / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018827:Carcinoma, Lewis Lung / Q000150:complications* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053580:Muscle Strength / Q000187:drug effects; D018908:Muscle Weakness / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009133:Muscular Atrophy / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D055435:Myostatin / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation; D051900:Smad3 Protein / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism; D013997:Time Factors
chemical_list: D000906:Antibodies; C525912:Mstn protein, mouse; D055435:Myostatin; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D013385:Succinate Dehydrogenase