Rapamycin did not prevent the excessive exercise-induced hepatic fat accumulation

Author(s):Show less -

Pinto, Ana P. ; da Rocha, Alisson L. ; Teixeira, Giovana R. ; Rovina, Rafael L. ; Veras, Allice S. C. ; Frantz, Fabiani ; Pauli, Jose R. ; de Moura, Leandro P. ; Cintra, Dennys E. ; Ropelle, Eduardo R. ; Quadrilatero, Joe ; da Silva, Adelino S. R.

• Document type: Journal article
• Source: Life Sciences; v. 306, p. 12-pg., 2022-07-15.

Abstract

Aims: The excessive eccentric exercise led to hepatic fat accumulation, which occurred concomitantly with elevation in the mammalian target of the rapamycin complex 1 (mTORC1) and insulin signaling pathways. Since mTORC1 and insulin can inhibit the autophagy pathway and explain the liver lipid content elevation, the main objective of the present investigation was to verify the responses of genes and proteins related to the autophagy and lipogenesis pathways in the hepatic tissue of mice submitted to the excessive downhill running protocol with and without rapamycin administration, a drug able to inhibit the mTORC1 pathway. Main methods: C57BL/6J mice were divided into four experimental groups: Control (CT; sedentary), Excessive exercise in downhill running (EE), Excessive exercise in downhill running with chronic administration of rapamycin (EE/Rapa), and Endurance exercise (END). At the end of the protocols, the blood and liver were collected for serum analysis, histology, immunohistochemistry, hepatic fat content, reverse transcription -quantitative polymerase chain reaction, and immunoblotting. Key findings: 1) higher levels of glucose, insulin, HOMA-IR, cortisol, ALT, and cholesterol, but lower levels of T4 for the EE/Rapa group; 2) hepatic fat accumulation for the EE and EE/Rapa groups; 3) upregulation of LC3 immunoexpression and downregulation of autophagic flux index for the EE and EE/Rapa groups; 4) reduction of P70S6K phosphorylation and SQSTM1 and increase of FOXO1A phosphorylation for the EE/Rapa group. Significance: The excessive exercise in downhill running with or without rapamycin led to increased liver fat content. Although rapamycin was effective in inhibiting mTORC1, the autophagy flux was not upregulated. (AU)

• FAPESP's process: 17/12765-2 - Emerging role of rev-erb-alpha in molecular adaptations to different physical exercise models
• Grantee: Alisson Luiz da Rocha
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 19/17058-8 - Role of interleukin-6 in the responses of the autophagic pathway in the heart of mice submitted in acute exhaustive physical exercise
• Grantee: Rafael Lemes Rovina
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 17/09038-1 - EFFECTS OF REGULAR PHYSICAL EXERCISE AND OVERTRAINING ON THE BEHAVIOR OF THE AUTOPHAGIC PATHWAY IN DIFFERENT TISSUES OF MICE.
• Grantee: Adelino Sanchez Ramos da Silva
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/00137-2 - Effects of physical exercise on the autophagy pathway
• Grantee: Adelino Sanchez Ramos da Silva
• Support Opportunities: Regular Research Grants
• FAPESP's process: 19/15428-2 - Role of autophagy in muscle stem cell differentiation
• Grantee: Ana Paula Pinto
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 17/19869-8 - Molecular mechanisms related to increased hepatic fat content in response to excessive physical exercise
• Grantee: Ana Paula Pinto
• Support Opportunities: Scholarships in Brazil - Doctorate