title: Complete reversal of muscle wasting in experimental cancer cachexia: Additive effects of activin type II receptor inhibition and β-2 agonist.
abstract: Formoterol is a highly potent β2-adrenoceptor-selective agonist, which is a muscle growth promoter in many animal species. Myostatin/activin inhibition reverses skeletal muscle loss and prolongs survival of tumor-bearing animals. The aim of this investigation was to evaluate the effects of a combination of the soluble myostatin receptor ActRIIB (sActRIIB) and the β2-agonist formoterol in the cachectic Lewis lung carcinoma model. The combination of formoterol and sActRIIB was extremely effective in reversing muscle wasting associated with experimental cancer cachexia in mice. Muscle weights from tumor-bearing animals were completely recovered following treatment and this was also reflected in the measured grip strength. This combination increased food intake in both control and tumor-bearing animals. The double treatment also prolonged survival significantly without affecting the weight and growth of the primary tumor. In addition, it significantly reduced the number of metastasis. Concerning the mechanisms for the preservation of muscle mass during cachexia, the effects of formoterol and sActRIIB seemed to be additive, since formoterol reduced the rate of protein degradation (as measured in vitro as tyrosine release, using incubated isolated individual muscles) while sActRIIB only affected protein synthesis (as measured in vivo using tritiated phenylalanine). Formoterol also increased the rate of protein synthesis and this seemed to be favored by the presence of sActRIIB. Combining formoterol and sActRIIB seemed to be a very promising treatment for experimental cancer cachexia. Further studies in human patients are necessary and may lead to a highly effective treatment option for muscle wasting associated with cancer.
authors.affiliation: Cancer Research Group, Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Míriam
authors.initials: M
authors.lastname: Toledo
authors.affiliation: Cancer Research Group, Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.|Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Busquets
authors.affiliation: Cancer Research Group, Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Fabio
authors.initials: F
authors.lastname: Penna
authors.affiliation: Departments of Metabolic Disorders and Protein Science, Amgen Research, Thousand Oaks, CA.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Cancer Research Group, Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Enrica
authors.initials: E
authors.lastname: Marmonti
authors.affiliation: Cancer Research Group, Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Angelica
authors.initials: A
authors.lastname: Betancourt
authors.affiliation: Cancer Research Group, Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Massa
authors.affiliation: Cancer Research Group, Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.|Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: López-Soriano
authors.affiliation: Departments of Metabolic Disorders and Protein Science, Amgen Research, Thousand Oaks, CA.
authors.forename: H Q
authors.initials: HQ
authors.lastname: Han
authors.affiliation: Cancer Research Group, Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.|Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Argilés
mesh_terms: D030301:Activin Receptors, Type II / Q000494:pharmacology*; D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D002100:Cachexia / Q000473:pathology / Q000517:prevention & control*; D018827:Carcinoma, Lewis Lung / Q000150:complications* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D000068759:Formoterol Fumarate / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B; D000068759:Formoterol Fumarate
keywords: ActRIIB; antimyostatin; cancer cachexia; formoterol; multitherapy; skeletal muscle