Small-molecule inhibition of MuRF1 protects against early disuse-induced diaphragmatic dysfunction and atrophy: Underlying cellular and molecular mechanisms

Background: Disuse-induced diaphragmatic dysfunction and atrophy (DIDD) is characterized by a rapid and progressive loss of diaphragm muscle fibers size and contractile function. Patients undergoing mechanical ventilation or diaphragm paralysis can develop DIDD, which correlates with worse clinical outcomes, morbidity and mortality. We hypothesize tha Muscle RING-finger protein-1 (MuRF1) activity plays an important role in DIDD onset and pathophysiology. Aim: To evaluate the effect of small-molecule inhibition of MuRF1 (MyoMed-205) on early DIDD in an experimental model in rats. Overall design: Male Wistar rats (n = 24) were divided into three experimental groups (n = 8): Sham 12h, Denervated 12h + vehicle, and Denervated 12h + MuRF1 inhibitor (205). Unilateral diaphragm denervation was performed, followed by intravenous treatment with vehicle or MuRF1 inhibitor (50 mg/kg bw) for 12h. The Sham operated group underwent no diaphragm denervation or aditional interventions apart from sedation and anesthesia. Diaphragm muscle (costal portion) was used for morphological, functional, gene (RNA-seq) and protein expression analyses.