Impaired calcium wave propagation underlies gallstone disease in mice fed a lithogenic diet
Morse, Harrison
Morse, Harrison
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Abstract
Abnormal motility is the hallmark of biliary tract disease, including both calculous and acalculous disorders. Gallstone disease is associated with elevated biliary cholesterol and hydrophobic salts, inflammation of the gallbladder wall and impaired gallbladder tone and contractility. In vitro studies have shown that both cholesterol and hydrophobic bile salts decrease excitability of gallbladder smooth muscles (GBSM), disrupting smooth muscle function through different mechanisms, but how these cellular abnormalities lead to decreased resting tone and weaker postprandial contractions in gallstone disease is not clear. To further elucidate the mechanisms leading to motor dysfunction in gallstone disease, we used Ca2+ imaging in mice fed a lithogenic diet or a normal chow for 1-8 weeks. In isolated gallbladders from mice fed a normal chow, GBSM cells within a single bundle exhibit rhythmic, synchronized Ca2+ events, corresponding to muscle action potentials. At the organ level, Ca2+ activity propagated as coherent waves across much of the visible bladder surface, often coactivating deeper orthogonally-arranged muscle layers. In mice fed a lithogenic diet, desynchronized GBSM Ca2+ activity, weaker contractile responses, changes in bile composition and presence of crystals were observed as early as 1 week - preceding inflammatory responses by at least a week. Ca2+ activity was more incoherent and random, usually presenting as activity in individual, separated fibers in superficial layers. Interestingly, individual GBSM fibers could maintain similar Ca2+ event frequency compared to controls, suggesting that impaired gallbladder motility is likely a result of changes in excitability and/or GBSM connectivity that limits how far Ca2+ activity can spread through gallbladder wall. The resulting incoherent and patchy activation of GBSM in mice fed lithogenic diet compromises the gallbladder�s ability to generate large propulsive forces - resulting in poorer mixing and emptying of bile that leads to gallstone disease.
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Date
1/1/2026
Student Status
Graduate Student
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Poster
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Neuroscience/Pharmacology
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College of Arts and Sciences
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Life Science