Poster, Podium & Video Sessions
Presentation Authors: Shelby A. Powers*, Terence E. Ryan, Michael R. Odom, Joseph M. McClung, Johanna L. Hannan, Greenville, NC
Introduction: Aging is associated with increased lower urinary tract symptoms including increased frequency and urgency. Impaired mitochondrial function is characteristic of aging and leads to impaired energy production and reactive oxygen species. These effects are implicated in pathological aging in multiple systems, including the genitourinary system. Knockout (KO) mice lacking polymerase gamma (POLG), a mitochondrial proofreading enzyme, display a premature aging phenotype and have been used to investigate the effects of aging on skeletal muscle and brain. This study characterized the accumulation of mitochondrial mutations on voiding function and bladder smooth muscle response in POLG KO mice.
Methods: Twelve month old male POLG KO (-/-) and genetically matched wild-type (WT) mice were evaluated for urinary voiding function. Bladders were weighed, urothelium removed and strips cut from the distal detrusor for tissue bath experiments. Contraction to carbachol and relaxation to norepinephrine (NE) were measured via concentration response curves. Contraction to electric field stimulation (EFS) was performed in the presence and absence of the cholinergic antagonist atropine.
Results: POLG KO mice exhibited increased bladder to body weight ratios (WT: 0.08% ± 0.003, KO: 0.10% ± 0.003; p<0.01). The prematurely aged mice demonstrated increased frequency (WT: 4 ± 0.7, KO: 6 ± 0.7; p<0.05) and total void area relative to body weight (WT: 1.3 cm2/g ± 0.22, KO: 2.1 ± 0.25; p<0.05), and smaller voids (WT: 14.4 cm2 ± 2.47, KO: 10.2 ± 0.86). Detrusor relaxation to NE and contraction to EFS was unchanged. However, sensitivity and maximal contraction to carbachol was decreased in KOs (p<0.05). Furthermore, cholinergic inhibition blunted EFS contraction 62% in WT and 35% in KOs indicating a greater purinergic neurotransmitter release was responsible for KO bladder contraction.
Conclusions: Aged bladders with accumulated mitochondrial mutations, are enlarged and exhibit smaller, more frequent voids and greater urine output. Additionally, KOs demonstrated less cholinergic mediated contraction and a shift to purinergic mediated EFS contraction. These findings signify the importance of further investigating the role of purinergic signaling and mitochondria in aging bladder dysfunction.
Source Of Funding: TER: HL129632; JMM: HL103797, HL125695