Formoterol reduces muscle wasting in mice undergoing doxorubicin chemotherapy

Edson Alves de Lima Junior; Alexandre Abilio de Souza Teixeira; Loreana Sanches Silveira; Queralt Jové; Natalia Álvarez Ladrón; Marcelo G Pereira; Francisco Javier López-Soriano; Josep M Argilés; Patrícia Chakur Brum; Silvia Busquets; José Cesar Rosa Neto

doi:10.3389/fonc.2023.1237709

Formoterol reduces muscle wasting in mice undergoing doxorubicin chemotherapy

Front Oncol. 2024 Jan 3:13:1237709. doi: 10.3389/fonc.2023.1237709. eCollection 2023.

Affiliations

¹ Immunometabolism Research Group, Department of Cell and Developmental Biology, University of São Paulo, São Paulo, Brazil.
² Cancer Research Group, Departament de Bioquímica i Molecular Biomedicine, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain and Institut de Biomedicina de la Barcelona (IBUB), Barcelona, Spain.
³ Leeds School of Biomedical Sciences, Faculty of Biological Sciences University of Leeds, Leeds, United Kingdom.
⁴ School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil.

^# Contributed equally.

Abstract

Background: Even though doxorubicin (DOX) chemotherapy promotes intense muscle wasting, this drug is still widely used in clinical practice due to its remarkable efficiency in managing cancer. On the other hand, intense muscle loss during the oncological treatment is considered a bad prognosis for the disease's evolution and the patient's quality of life. In this sense, strategies that can counteract the muscle wasting induced by DOX are essential. In this study, we evaluated the effectiveness of formoterol (FOR), a β2-adrenoceptor agonist, in managing muscle wasting caused by DOX.

Methods and results: To evaluate the effect of FOR on DOX-induced muscle wasting, mice were treated with DOX (2.5 mg/kg b.w., i.p. administration, twice a week), associated or not to FOR treatment (1 mg/kg b.w., s.c. administration, daily). Control mice received vehicle solution. A combination of FOR treatment with DOX protected against the loss of body weight (p<0.05), muscle mass (p<0.001), and grip force (p<0.001) promoted by chemotherapy. FOR also attenuated muscle wasting (p<0.01) in tumor-bearing mice on chemotherapy. The potential mechanism by which FOR prevented further DOX-induced muscle wasting occurred by regulating Akt/FoxO3a signaling and gene expression of atrogenes in skeletal muscle.

Conclusions: Collectively, our results suggest that FOR can be used as a pharmacological strategy for managing muscle wasting induced by DOX. This study provides new insights into the potential therapeutic use of FOR to improve the overall wellbeing of cancer patients undergoing DOX chemotherapy.

Keywords: Lewis lung carcinoma; beta2-adrenergic agonist; chemotherapy; doxorubicin; muscle wasting.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was funded by The São Paulo Research Foundation (FAPESP grant number 2015/17068-2; 2019/01244-7; 2013/09367-4; 2019/09854-9), Coordination of Superior Level Staff Improvement (CAPES), and National Council for Scientific and Technological Development (CNPQ). This work was also supported by a grant from the Ministerio de Economia y Competitividad from Spain (SAF2015-65589-P).