Mitochondrial oxidative substrate selection in porcine bladder smooth muscle

Purpose: Alterations in bladder smooth muscle (BSM) metabolism due to alterations in plasma lipid levels may be important with the increasingly high fat diets eaten by most Americans. To determine the susceptibility of BSM to lipotoxicity we examined the normal pattern of mitochondrial substrate selection in BSM and the ability of BSM to respond to changes in metabolic substrate provision. Materials and Methods: BSM strips were incubated in 5 mM 1-C-13-glucose and 0 to 5 mM 1,2-C-13-acetate. The pattern of substrate use measured by C-13-nuclear magnetic resonance using BSM extracts. BSM was also cultured for 4 days to elicit changes in cell phenotype. Results: At physiological levels of glucose and acetate about 50% of the substrate used by mitochondria was glucose. When acetate concentration was changed from physiological levels (0.1 mM) to pathophysiological levels (0.5 mM), BSM was able to increase the use of acetate, while sparing the use of glucose and intracellular substrates, likely lipids. Above 0.5 mM acetate BSM was unable to further use acetate. With increasing acetate use anaplerosis increased, consistent with a depletion of tricarboxylic acid cycle intermediates. After 4 days of organ culture BSM mitochondria used significantly more unlabeled intracellular substrates and less C-13 labeled glucose than control bladder, consistent with metabolic adaptation to increase lipid use, such as what occurs with hyperlipidemia. Conclusions: We conclude that BSM has modest plasticity of the pattern of mitochondrial substrate selection and excess lipid provision may be able to induce lipotoxicity in BSM, resulting in impaired detrusor function.