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Effect of calstabin1 depletion on calcium transients and energy utilization in FDB muscle fibers and potential treatment opportunities based on RyR1 stabilizers

Breckner, Anke and Gerwin, Nicole and Richter, Jens and Rausch, Martin and Marcellin, David and Ganz, Magdalena (2013) Effect of calstabin1 depletion on calcium transients and energy utilization in FDB muscle fibers and potential treatment opportunities based on RyR1 stabilizers. The Journal of Biological Chemistry, 8 (11). ISSN 1932-6203

Official URL: http://www.jbc.org

Abstract

Depletion of calstabin1 from the RyR1 channel leading to calcium leakage from the sarcoplasmic reticulum (SR) into the cytoplasm is found in certain conditions such as dystrophy, aging or muscle overuse. The first aim of this study was to assess the effect of calstabin1 depletion on calcium baseline levels and transients. We found that depletion of calstabin1 by FK506 slowed down the reuptake of calcium into the SR by 14 % after tetanic activation (50Hz, 300ms). However, we could not observe a significant increase of cytoplasmic calcium baseline levels. Therefore, we tested if increased SERCA activity would counterbalance calcium leakage by measuring the energy utilization of muscle fibers with and without FK506 treatment. Here, we observed that FK506 led to an increase of oxygen consumption by 125 % compared to baseline levels. Finally, we found that pretreatment of muscle fibers with the calstabin1 stabilizer JTV-519 led to an almost complete normalization of calcium flux dynamics and energy utilization. We conclude that cytosolic calcium levels are mostly preserved in conditions with leaky RyR1 channel most probably due to increased SERCA activity. Moreover, one can hypothesize that RyR1 leakiness might lead to chronic metabolic stress potentially followed by cellular damage and that RyR1 stabilizers could potentially be used to protect muscle tissue under the before mentioned disease conditions.

Item Type: Article
Keywords: muscle fiber; RyR1; calstabin1; calcium; 2-photon microscopy
Date Deposited: 26 Apr 2016 23:46
Last Modified: 26 Apr 2016 23:46
URI: https://oak.novartis.com/id/eprint/9411

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