Physical exercise as a circadian rhythm synchronizer in cancer.

Author(s)

Alexandre Abilio de Souza Teixeira

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2020-12-04

Examining board members

José Cesar Rosa Neto; Alison Colquhoun; Valdir de Aquino Lemos; Fábio Santos de Lira

• Advisor: José Cesar Rosa Neto

Abstract

Background: Changes in circadian rhythm are related to cancer development and growth, however the molecular mechanisms underlying this effect need to be further studied. It is known that physical exercise can synchronize the circadian rhythm, since it acts in the modulation of the psychoneuroimmunoendocrine system. The development of the tumor, in turn, promotes changes in the balance of this system resulting in a disturbance of the circadian rhythm. Thus a regular exercise program can be a useful and a low-cost intervention as a strategy to improve the quality of life of cancer patients and survivors. Therefore, our objective was to evaluate whether the mechanisms involved in the inhibition of tumor growth by physical training can be correlated with the chronological role of physical exercise. Methods: C57BL / 6J mice were used, divided into 4 groups: control (CTL); Tumor (LLC); Tumor + Training at the same time of day (LLC + TZT2); Tumor + Training at alternate times (LLC + TZTAlt). The animals were submitted to aerobic training on the third day after tumor inoculation. 14 training sessions were carried out comprising 5 sessions / week (40 to 60 minutes at 60% of maximum speed). The animals were euthanized 21 days after inoculating the tumor, every 4 hours of the day, until completing 24 hours (ZT0, ZT4, ZT8, ZT12, ZT16 and ZT20). In the gastrocnemius muscle, analyzes of the gene expression of the clock genes were performed (Clock, Bmal1, Per1, Per2, Per3, Cry1, Cry2, REV-ERB &#945, Ror &#945 and Ror &#946 ), Ampk, Atrogin-1, Murf1 and GAPDH. The determination of the concentration of TNF- &#945 , IL-1 &#946 , MCP-1, IFN-, VEGF, IL-10 and IL-4 were performed in the gastrocnemius muscle and in the tumor. Results: The training reduced the total weight when compared with the LCC group, and only the LLC + T(ZTAlt) had a reduction in weight when compared with the CTL group. The tumor weight was lower in the LLC+T(ZTAlt) group when compared to the LLC group. The EDL and soleus muscles presented greater weight in the ZT2 group when compared to the LLC group. Exercise at different times also reduced glucose concentration when compared to the LLC group (ZT8). The physical training practiced at alternated times was able to increase the expression in the Per1 gene (ZT4) when compared with sedentary groups. The group that trained in ZT2 had an increase in Per2 expression when compared with the CTL group in ZT0 and ZT4, whereas the group with alternate training showed an increase in Per2 when compared with the CTL and LLC group only in ZT4. On the Per3 gene, the LLC+T (ZTAlt) group showed a higher expression in ZT4 when compared with the CTL and LLC groups. The gene expression of AMPK was increased in the light period and Atrogin-1 reduced, both in the LLC+T(ZT2) group. Atrogin-1 was increased in the LLC+T(ZTAlt) group in the ZT20 when compared to the CTL group. Also in the gastrocnemius muscle, the protein expression of TNF- was higher in the LLC group (ZT16) when compared with the CTL and LLC+T(ZTAlt). VEGF was increased in the LLC group when compared to the LLC+T(ZTAlt). IL-10(ZT16) was increased in the LCC group when compared to the CTL and LLC+T groups (ZT2 and Alt). In the same ZT, the LLC+T(ZTAlt) group showed a lower expression of IL-10 when compared to the CTL and LLC + T(ZT2) group. IL-4 showed an increase in ZT16 expression in the LLC +T(ZT2) group when compared with the CTL and LLC+T(ZTAlt) groups. In the tumor, TNF- &#945 was affected by exercise, being increased in the group that trained at alternate times (ZT16) when compared with the LLC+T(ZT2). And IL-10 and IL-4 were also more expressed in alternate exercise (ZT4). Conclusion: Physical exercise proved to be a major modulator of the circadian clock in skeletal muscle, promoting protective effects to the muscle, in addition to attenuating tumor growth. (AU)

• FAPESP's process: 15/16777-0 - Physical exercise as a synchronizer of circadian rhythms in cancer
• Grantee: Alexandre Abilio de Souza Teixeira
• Support Opportunities: Scholarships in Brazil - Doctorate