Presentation Authors: Hanna Kosnik, Michael Odom, Elena Pak, Kelsey Fisher-Wellman, Johanna Hannan*, Greenville, NC
Introduction: Obesity increases the prevalence of bladder dysfunction in both males and females. The bladderâ€™s mucosal and detrusor smooth muscle layers are involved in bladder signaling and contraction, respectively. The underlying causes of obesity-induced bladder dysfunction in males and females are poorly understood. Mitochondrial dysfunction is common in the heart, liver and skeletal muscle with high fat diet. This study aims to determine the impact of long-term high fat diet (HFD) on bladder mucosal and detrusor mitochondrial respiration in male and female mice.
Methods: Adult male and female mice were fed a control (10% kcal fat) or HFD (45% kcal fat; n=7/group) for 24 weeks. Bladders were collected, weighed and separated into mucosal and detrusor layers. Tissues were cut into strips, permeabilized, and placed in an OROBOROS Oxygraphy-2K to measure respiration. Substrates (pyruvate/malate, glutamate, L-octanoylcarnitine/malate, or succinate/rotenone) were added with increasing concentrations of phosphocreatine for substrate-specific force-flow bioenergetic analysis. Respiratory conductance, the rate of change in respiration, was measured with increasing phosphocreatine concentration. Respiratory conductance is analogous to the cellâ€™s responsiveness to create ATP with respect to the substrate.
Results: Chronic HFD increased body weight and decreased the bladder to body weight ratio in both sexes compared to control mice. Male HFD mucosal and detrusor force-flow respiration and respiratory conductance was decreased in the presence of fatty acid substrate L-octanoylcarnitine/malate. HFD male force-flow respiration and respiratory conductance was unchanged in the presence of pyruvate/malate, glutamate, and succinate/rotenone. In HFD females, force-flow respiration and respiratory conductance were unchanged in presence of pyruvate/malate, glutamate, and L-octanoylcarnitine/malate. However, HFD female mucosal layer had decreased force-flow respiration with succinate/rotenone but no change in respiratory conductance.
Conclusions: Male mice chronically fed a HFD have decreased fatty acid metabolism within the mucosal and detrusor muscle layers whereas female mice are protected. Ongoing studies will determine if the excess lipids are accumulating within the bladder and if we can rescue fatty acid metabolism with co-factors such as L-carnitine or acetyl-CoA. Understanding bladder metabolic and bioenergetic sex differences will help to create more effective treatments for bladder dysfunction.
Source of Funding: DiaComp Pilot and Feasibility Grant, American Physiology Society Undergraduate Summer Research Fellowship