Effects of the pharmacological inhibition of MurF upon ventilator-induced diaphragmatic atrophy and dysfunction in rats

• Grant number: 20/04607-0
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: July 01, 2020
• End date: April 30, 2026
• Field of knowledge: Biological Sciences - Morphology - Anatomy
• Principal Investigator: Anselmo Sigari Moriscot
• Grantee: Fernando Silva Ribeiro
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated scholarship(s): 22/14495-0 - Investigation of MuRF1 chemical knockdown therapeutic potential for ventilator-induced diaphragmatic dysfunction in experimental ICU model, BE.EP.DD

Abstract

Prolonged mechanical ventilation induces diaphragmatic atrophy and dysfunction, a progressive clinical condition with rapid onset, which is often associated with ventilation weaning failure and high mortality in critical ill patients. The comprehension of the biological mechanisms involved in ventilator-induced diaphragmatic atrophy and dysfunction is essential to the development of effective therapies. It is known that the increase of MuRF E3 ligase activity and protein breakdown by ubiquitin-proteasome system is one of the main mechanisms involved on the development of this condition. Moreover, recent evidences show that MuRF1 knockout mice are protected against the development of diaphragmatic atrophy and dysfunction, being MuRF1, therefore, a potential therapeutic target. Nevertheless, the impact and therapeutic potential of the pharmacological inhibition of MuRF upon the ventilator-induced diaphragmatic atrophy and dysfunction is yet unknow. Therefore, the general aim of this study is to investigate the effects of the MCEMBL#205 compound, a new pharmacological inhibitor of MuRF, upon ventilator-induced diaphragmatic atrophy and dysfunction in rats. Our specific aims are: 1) To test the effects of different doses of the MCEMBL#205 on biomarkers of MuRF activity in diaphragm; analyze the effects of MCEMBL#205 upon: 2) diaphragm muscle contractility; 3) diaphragm muscle mass; 4) transcriptional regulators of MuRF; 5) biomarkers of protein synthesis; 6) biomarkers of protein breakdown; 7) biomarkers of oxidative stress; and 8) calcium handling proteins in diaphragm. This study will contribute to a better understanding regard the biological effects of the MCEMBL#205 on diaphragm, and for your potential clinical translation and eventual therapeutic use in humans. (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)

RIBEIRO, F.; VIEIRA, C.; LABEIT, S.; MORISCOT, A.. Small-Molecule Mediated Chemical Knockdown of Muscle RING-Finger Protein 1 (MuRF1) Prevents Diaphragm Dysfunction Induced by Mechanical Unloading Driven by Unilateral Denervation. American Journal of Respiratory and Critical Care Medicine, v. 205, p. 1-pg., 2022-05-01. (20/04607-0)

RIBEIRO, FERNANDO; ALVES, PAULA K. N.; BECHARA, LUIZ R. G.; FERREIRA, JULIO C. B.; LABEIT, SIEGFRIED; MORISCOT, ANSELMO S.. Small-Molecule Inhibition of MuRF1 Prevents Early Disuse-Induced Diaphragmatic Dysfunction and Atrophy. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 24, n. 4, p. 17-pg., 2023-02-01. (20/04607-0, 21/03066-9)