Effect of leucine on the expression of miR-299A and HDAC4 in the skeletal muscle of rats submitted to immobilization: implications for the control of muscle mass

• Grant number: 18/24419-4
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Effective date (Start): January 01, 2019
• Effective date (End): September 30, 2021
• Field of knowledge: Biological Sciences - Morphology - Anatomy
• Principal Investigator: Anselmo Sigari Moriscot
• Grantee: Paula Ketilly Nascimento Alves
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 15/04090-0 - Identification and caracterization of mechanisms involved in skeletal muscle mass control and regeneration, AP.TEM

Abstract

Skeletal muscle tissue has great influence on the performance of activities and the individual's functionality in the environment. This tissue has a high plasticity, which allows adaptation of its structure and function in response to different anabolic and catabolic stimuli. Catabolic stimuli lead to muscle atrophy and can be upregulated by post-transcriptional modification mediated by Histone Deacetylases (HDACs) leading to increased transcription of key mediators (Atrogin-1 and Murf1) of muscle atrophy. However, leucine, an amino acid that promotes important anti-catabolic actions, has been used to attenuate protein catabolism during immobilization in order to preserve muscle mass; in addition, leucine may be involved in the activation of microRNAs that repress the expression of genes at the post-transcriptional level. Thus the purpose of this study is to investigate whether the protective role of leucine during atrophy is related to the induction of miR299A expression and its impact on the deacetylation process, leading to the inhibition of atrogenes. To do this, first, Wistar rats will be immobilized and supplemented with leucine orally via gavage for 3 and 7 days to analyze the tissue location of HDAC4, its gene expression and relation to leucine, as well as targets involved in the atrophic process. In addition, C2C12 cells treated with dexamethasone will be used later to evaluate the effects of leucine on the expression of HDAC4 in an atrophic model in vitro. In the analysis of deep sequencing carried out by us it was possible to verify the expressive drop of miR-299A during immobilization and reversion of this state when supplemented with leucine, in this way we will also analyze the tissue expression of this miRNA in immobilized and leucine treated rats and investigate if this is a direct target of HDAC4. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

ALVES, PAULA K. N.; CRUZ, ANDRE; SILVA, WILLIAM J.; LABEIT, SIEGFRIED; MORISCOT, ANSELMO S.. Leucine Supplementation Decreases HDAC4 Expression and Nuclear Localization in Skeletal Muscle Fiber of Rats Submitted to Hindlimb Immobilization. CELLS, v. 9, n. 12, DEC 2020. (15/04090-0, 18/24419-4, 17/09398-8)

CRUZ, ANDRE; FERIAN, ANDREA; ALVES, PAULA K. N.; SILVA, WILLIAM JOSE; BENTO, MIRELLA RIBEIRO; GASCH, ALEXANDER; LABEIT, SIEGFRIED; MORISCOT, ANSELMO SIGARI. Skeletal Muscle Anti-Atrophic Effects of Leucine Involve Myostatin Inhibition. DNA AND CELL BIOLOGY, v. 39, n. 12, NOV 2020. (12/22488-2, 13/19387-2, 15/04090-0, 17/09398-8, 18/24419-4)