Targeting mitochondria to prevent obesity induced bladder dysfunction
One of the most common and debilitating complications of obesity is diabetic bladder dysfunction which significantly impacts the quality of life of diabetic patients and has a large medical financial burden. The pathophysiology of bladder dysfunction during type 2 diabetes mellitus (T2DM) impacts the urothelium, smooth muscle and/or the autonomic nerves. T2DM bladder dysfunction is associated with increased inflammation, hypoxia and neurovascular dysfunction all of which may affect tissue function. However, at this time no pathological mechanism has been identified that can explain completely the onset of diabetic bladder dysfunction, thus hindering the development of an effective treatment. Our preliminary experiments demonstrated that mice chronically fed a high fat diet (HFD, 45% kcal from fat) had increased diuresis and electrical field stimulated (EFS) mediated contraction, which was associated with impaired mitochondrial respiration and increased hydrogen peroxide (H2O2) production potential in the detrusor. Based on the results of our preliminary experiments, our objective is to focus on the energetics of the mitochondria as a primary driver of bladder dysfunction during HFD-induced T2DM. We propose to test the novel hypothesis that the development of bladder dysfunction is the result increased mitochondrial respiration and increased ROS emission in the bladder tissue. To meet our objective, we have developed a novel approach for assessing respiratory function of the bladder, in which we can determine O2 respiration with minimal disruption to the anatomical structure of the bladder or native biochemical arrangement of the mitochondria. We will examine our hypothesis with the following 2 aims. In Aim 1, we will evaluate the contribution of reduced mitochondrial respiration in the urothelium and detrusor smooth muscle from mice fed a short or chronic HFD to alterations in bladder function. In Aim 2, we will determine the ability of mitochondrial catalase overexpression to prevent HFD-induced bladder dysfunction. A multidisciplinary team science approach has been used in this proposal to study the role of bladder mitochondrial function in obesity-induced T2DM symptoms of urinary incontinence. We anticipate that these studies will help elucidate the mechanism of bladder dysfunction that occurs during HFD-induced type 2 diabetes.