erobic Exercise Training and In Vivo Akt Activation Counteract Cancer Cachexia by Inducing a Hypertrophic Profile through eIF-2 alpha Modulatio

Author(s):Show less -

Pereira, Marcelo G. ^{[1, 2]} ; Voltarelli, Vanessa A. ^{[1, 3, 4]} ; Tobias, Gabriel C. ^{[1, 5, 6]} ; de Souza, Lara ^[1] ; Borges, Gabriela S. ^[1] ; Paixao, Ailma O. ^[1] ; de Almeida, Ney R. ^[1] ; Bowen, Thomas Scott ^[2] ; Demasi, Marilene ^[7] ; Miyabara, Elen H. ^{[1, 8]} ; Brum, Patricia C. ^[1]

Affiliation

^[1] Univ Sao Paulo, Sch Phys Educ & Sport, BR-05508030 Sao Paulo - Brazil

^[2] Univ Leeds, Fac Biol Sci, Leeds Sch Biomed Sci, Leeds LS2 9JT, W Yorkshire - England

^[3] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Surg, Boston, MA 02115 - USA

^[4] Siriolibanes Hosp, BR-01308050 Sao Paulo - Brazil

^[5] Weill Cornell Med, Meyer Canc Ctr, Childrens Canc & Blood Fdn Labs, Drukier Inst Childrens Hlth, Dept Pediat, New York, NY 10021 - USA

^[6] Weill Cornell Med, Meyer Canc Ctr, Childrens Canc & Blood Fdn Labs, Drukier Inst Childrens Hlth, Dept Cell & Dev Biol, New York, NY 10021 - USA

^[7] Butantan Inst, Biochem & Biophys Lab, BR-05503900 Sao Paulo - Brazil

^[8] Univ Sao Paulo, Inst Biomed Sci, Dept Anat, BR-05508000 Sao Paulo - Brazil

• Document type: Journal article
• Source: CANCERS; v. 14, n. 1 JAN 2022.
• Web of Science Citations: 0

Abstract

Simple Summary:\& nbsp;Chronic disease-related muscle atrophy is a serious public health problem since it reduces mobility and contributes to increases in hospitalization costs. Unfortunately, there is no approved treatment for muscle wasting at present. Thus, an understanding of the mechanisms underlying the control of muscle mass and function under chronic diseases can pave the way for the discovery of innovative therapeutic strategies to counteract muscle wasting. Since numerous types of cancer induce cachexia, which has no cure nor an effective treatment, the main proposal here was to study the effects of AET in cancer cachexia, and to investigate, through in vivo manipulation of the Akt/mTORC1 pathway, whether the cachectic muscle still presents conditions to respond adaptively to hypertrophic stimuli. Our results could provide a basis for innovative research lines to better understand muscle plasticity and to investigate potential therapeutic approaches necessary to prevent muscle loss.\& nbsp;Cancer cachexia is a multifactorial and devastating syndrome characterized by severe skeletal muscle mass loss and dysfunction. As cachexia still has neither a cure nor an effective treatment, better understanding of skeletal muscle plasticity in the context of cancer is of great importance. Although aerobic exercise training (AET) has been shown as an important complementary therapy for chronic diseases and associated comorbidities, the impact of AET on skeletal muscle mass maintenance during cancer progression has not been well documented yet. Here, we show that previous AET induced a protective mechanism against tumor-induced muscle wasting by modulating the Akt/mTORC1 signaling and eukaryotic initiation factors, specifically eIF2-alpha. Thereafter, it was determined whether the in vivo Akt activation would induce a hypertrophic profile in cachectic muscles. As observed for the first time, Akt-induced hypertrophy was able and sufficient to either prevent or revert cancer cachexia by modulating both Akt/mTORC1 pathway and the eIF-2 alpha activation, and induced a better muscle functionality. These findings provide evidence that skeletal muscle tissue still preserves hypertrophic potential to be stimulated by either AET or gene therapy to counteract cancer cachexia. (AU)

• FAPESP's process: 16/26169-0 - Potential therapeutic targets induced by aerobic exercise training for the treatment of cancer cachexia: a study of ribosomal proteins
• Grantee: Marcelo Gomes Pereira
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 17/13133-0 - Relative role of physical activity on mitochondrial density and bioenergetics of infiltrating T lymphocytes from tumor microenvironment
• Grantee: Vanessa Azevedo Voltarelli
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 20/12279-3 - Effect of aerobic physical training on sympathetic nervous activity on skeletal muscle and tumoral tissue in Cancer cachexia
• Grantee: Gabriela Silva Borges
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 15/22814-5 - Cancer and heart: new paradigms of diagnosis and treatment
• Grantee: Carlos Eduardo Negrão
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 18/02351-9 - Role of microRNAs to the attenuation of the colon tumor growth induced by aerobic physical activity in mice
• Grantee: Gabriel Cardial Tobias
• Support Opportunities: Scholarships in Brazil - Doctorate