Saturday, November 23, 2024
11/23/2024
Abstract Diaphragm weakness is a significant health problem in patients with chronic heart failure and reduced ejection fraction (HFrEF). The topic is relevant because respiratory muscle dysfunction impairs coughing and predisposes patients with HFrEF to pneumonia, activates the sympathetic nervous system causing cardiac arrhythmias and peripheral vasoconstriction, and impairs alveolar ventilation during exercise and contributes to shortness of breath and exercise intolerance. A mismatch in production and scavenging of reactive oxygen species (ROS), accompanied by oxidative modifications of contractile, mitochondrial, and cell signaling proteins, is a critical determinant of diaphragm abnormalities in HFrEF. Our previous studies suggest that putative mechanisms for diaphragm fiber atrophy/weakness, contractile dysfunction, and fatigue in HFrEF are an impairment in protein synthesis/degradation and mitochondrial dysfunction. Moreover, several studies indicate that diaphragm abnormalities contribute to exercise intolerance in HFrEF, although this postulate has never been tested with diaphragm specific interventions. In this proposal, our goal is to identify the redox- mediated and protein oxidation mechanisms which are causative in diaphragm fiber atrophy and mitochondrial dysfunction in HFrEF and define the role of diaphragm abnormalities on exercise tolerance in HFrEF. To achieve this goal, the diversity candidate will perform perform experiments in in two specific aims. Aim 1 will test the hypothesis that overexpression of specific oxidized protein reductases prevent ROS-induced impairments in critical regulators of protein synthesis, mitochondrial respiration and H2O2 emission, and diaphragm contractile dysfunction ex vivo. These experiments will be performed in myotubes and diaphragm bundles from healthy sham-operated animals (parent award). Aim 2 will determine whether diaphragm myocyte-specific overexpression of oxidized protein reductases prevent HFrEF-induced impairments in critical regulators of protein synthesis, mitochondrial function, and exercise intolerance. Aim 2 will also include a depper analysis of global and redox proteomics focused on regulation of protein synthesis/degradation. The experiments in Aim 2 will be performed in sham and HFrEF animals (parent award). To gain further insights into mechanisms of contractile dysfunction, the candidate will perform measurements of single fiber ATPase activity during contraction. The project is a logical extension of the parent award that will give deeper insights into the mechanisms of diaphragm abnormalities in HFrEF. Importantly, the project will provide training in original research covering a broad spectrum of topics (cell biology, redox biochemistry, muscle physiology, - omics, and translational research) under the supervision of a mentoring team with member at several career stages career stages (Assistant, Associate, and Full Professor) provide a comprehensive preparation of the diversity candidate for a career as independent investigator.
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