Resistance Training Attenuates Activation of STAT3 and Muscle Atrophy in Tumor-Bearing Mice

Mayra Tardelli de Jesus Testa; Paola Sanches Cella; Poliana Camila Marinello; Fernando Tadeu Trevisan Frajacomo; Camila de Souza Padilha; Patricia Chimin Perandini; Felipe Arruda Moura; José Alberto Duarte; Rubens Cecchini; Flavia Alessandra Guarnier; Rafael Deminice

doi:10.3389/fonc.2022.880787

Resistance Training Attenuates Activation of STAT3 and Muscle Atrophy in Tumor-Bearing Mice

Front Oncol. 2022 Jul 1:12:880787. doi: 10.3389/fonc.2022.880787. eCollection 2022.

Affiliations

¹ Department of Physical Education, State University of Londrina, Londrina, Brazil.
² Department of General Pathology, State University of Londrina, Londrina, Brazil.
³ Program of Molecular Carcinogenesis, Brazilian National Institute of Cancer, Rio de Janeiro, Brazil.
⁴ Department of Physical Education, State University of São Paulo (UNESP), Presidente Prudente, Brazil.
⁵ Faculty of Sport, University of Porto, CIAFEL, Porto, Portugal.

Abstract

Purpose: Although the role of signal transducers and activators of transcription (STAT3) in cachexia due to the association of circulating IL-6 and muscle wasting has been extensively demonstrated, the effect of resistance training on STAT3 in mediating muscle atrophy in tumor-bearing mice is unknown. The aim of this study is to investigate the effects of resistance exercise training on inflammatory cytokines and oxidative-mediated STAT3 activation and muscle loss prevention in tumor-bearing mice.

Methods: Male Swiss mice were inoculated with Ehrlich tumor cells and exposed or not exposed to resistance exercise protocol of ladder climbing. Skeletal muscle STAT3 protein content was measured, compared between groups, and tested for possible association with plasma interleukins and local oxidative stress markers. Components of the ubiquitin-proteasome and autophagy pathways were assessed by real-time PCR or immunoblotting.

Results: Resistance training prevented STAT3 excessive activation in skeletal muscle mediated by the overabundance of plasma IL-6 and muscle oxidative stress. These mechanisms contributed to preventing the increased key genes and proteins of ubiquitin-proteasome and autophagy pathways in tumor-bearing mice, such as Atrogin-1, LC3B-II, and Beclin-1. Beyond preventing muscle atrophy, RT also prevented strength loss and impaired locomotor capacity, hallmarks of sarcopenia.

Conclusion: Our results suggest that STAT3 inhibition is central in resistance exercise protective effects against cancer-induced muscle atrophy and strength loss.

Keywords: autophagy; cancer cachexia; muscle wasting; strength; ubiquitin-proteasome.