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Interplay betweeen myostatin and mTORC1 pathways in skeletal muscle: implications for a thyroid hormone biological action

Grant number: 17/09398-8
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): June 01, 2017
Effective date (End): September 30, 2021
Field of knowledge:Biological Sciences - Morphology - Anatomy
Principal researcher:Anselmo Sigari Moriscot
Grantee:André Cruz de Oliveira
Home 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
Associated scholarship(s):19/06819-8 - Impact of MuRF-1 and MuRF-2 to skeletal muscle wasting under experimental hyperthyroidism, BE.EP.DD

Abstract

Thyroid hormones play a key role in a broad range of cellular processes, impacting development, growth and differentiation. The active form of these hormones (T3) can inhibit or induce gene transcription by its genomic or non-genomic effects. Although it is clear that in skeletal muscle high levels of T3 can induce increased proteolysis, the resulting atrophy can also be associated with synthesis inhibition. One of the main pro-synthesis pathways is Akt/mTOR, although the knowledge about its status on skeletal muscle under T3 action remains scarce. In addition, it is known that the Akt/mTOR pathway is under the negative control of the myostatin pathway throughout TORC1, however the molecular mechanisms whereby this process occurs is not yet well established. A microarray analysis shows that Raptor is down regulated by T3, this subunit is fundamental for the mTORC1 function and so protein synthesis. Therefore, this work aims to address the myostatin pathway action under Akt/mTOR activity on skeletal muscle during experimentally induced hyperthyroidism. For that, Wistar rats were treated with 20 physiological doses of T3 for 0.5, 1, 7 and 14 days. We could observe a rigorous cardiac hypertrophy, and several alterations at skeletal muscle, such as diminished muscle mass associated with small fibers after 14 days under T3 doses. A qPCR analysis showed a fast inhibition on Follistatin mRNA levels and interestingly this gene is an endogenous inhibitor of myostatin. On the other hand, myostatin itself shows a rapid and robust increase in expression after hormonal treatment, suggesting a bigger impact on mTORC1. Supporting this hypothesis we show that protein expression of major components of mTORC1 pathway were down regulated, Raptor, mTOR phosphorylated and P70S6k phosporylated. These results highlight that altering the myostatin pathway by manipulating miRNAs expression in vivo and in vitro, could be used as therapeutic tools aiming to restore the mTORC1 function. This could provide potential to revert the atrophic phenotype or even induce T3 dependent hypertrophic effects on skeletal muscle. Subsequently primary culture of myogenic cells will be treated with T3 and then the Akt/mTOR pathway will be inhibited with wortmannin and the myostatin pathway with an interference RNA. We will then measure: 1) the transversal sectional area of the fibers; 2) the gene expression of all pathways components and 3) further its phosporylation patter. Previous analysis of a microarray dataset suggests donw-regulation of Raptor induced by T3, potentially affecting translation. Furthermore, T3 treatment drove a down-regulation of Follistatin, an inhibitor of the myostatin pathway, suggesting increased myostatin activity upon its receptor. (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. Web of Science Citations: 0.
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. Web of Science Citations: 0.
RAMOS, G. V.; CRUZ, A.; SILVA, W. J.; ROZANSKI, A.; BAPTISTA, I. L.; SILVESTRE, J. G.; MORISCOT, A. S. Thyroid hormone upregulates MDM2 in rat type I fibre: Implications for skeletal muscle mass regulation. ACTA PHYSIOLOGICA, v. 222, n. 4 APR 2018. Web of Science Citations: 1.

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