Investigation of MuRF1 chemical knockdown therapeutic potential for ventilator-induced diaphragmatic dysfunction in experimental ICU model

• Grant number: 22/14495-0
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: September 01, 2023
• End date: August 31, 2024
• Field of knowledge: Biological Sciences - Morphology - Anatomy
• Principal Investigator: Anselmo Sigari Moriscot
• Grantee: Fernando Silva Ribeiro
• Supervisor: Lars Larsson
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Karolinska Institutet, Sweden
• Associated to the scholarship: 20/04607-0 - Effects of the pharmacological inhibition of MurF upon ventilator-induced diaphragmatic atrophy and dysfunction in rats, BP.DD

Abstract

Mechanical ventilation (MV) is a life-saving intervention commonly used in intensive care units (ICUs) for patients who cannot independently maintain adequate gas exchange. However, long-term MV results in detrimental clinical effects, including skeletal muscle weakness and wasting. Ventilator-induced diaphragmatic dysfunction (VIDD) is the early and progressive loss of diaphragm muscle contractile force and mass, representing a major concern for critically ill patients. The early up-regulation of the ubiquitin-proteasome system is a key mechanism involved in the increased diaphragmatic myofibrillar proteins disruption and degradation, contributing to VIDD. Data from animal and human studies supports that MV causes early up-regulation of Muscle RING-finger Protein 1 (MuRF1) expression. Over 50 substrates of MuRF1 ubiquitination have been identified, including myofibrillar and sarcoplasmic proteins. Despite this, the contribution of MuRF1 to VIDD's early development and further progression remains poorly understood. Yet, data from a single animal study has suggested that MuRF1 knockout (KO) mice showed full protection against VIDD following six hours of MV. In this regard, MuRF1-targeting pharmacological interventions can potentially become a therapeutic strategy for treating VIDD. This study proposes to investigate the effects of MuRF1 chemical knockdown, induced by MyoMed-205, a novel small-molecule designed to inhibit MuRF1's activity, upon ventilator-induced diaphragmatic dysfunction in the experimental ICU model. (AU)