Effect of Calstabin1 Depletion on Calcium Transients and Energy Utilization in Muscle Fibers and Treatment Opportunities with RyR1 Stabilizers

Breckner, Anke; Ganz, Magdalena; Marcellin, David; Richter, Jens; Gerwin, Nicole; Rausch, Martin

Effect of Calstabin1 Depletion on Calcium Transients and Energy Utilization in Muscle Fibers and Treatment Opportunities with RyR1 Stabilizers

Files

Breckner_2-189och74002q66.pdf(679.34 KB)

Date

2013

Authors

Breckner, Anke

Ganz, Magdalena

Marcellin, David

Richter, Jens

Gerwin, Nicole

Rausch, Martin

Publication type

Journal article

Publication status

Published

Published in

PLoS one ; 8 (2013), 11. - e81277. - eISSN 1932-6203

Abstract

Depletion of calstabin1 (FKBP12) from the RyR1 channel and consequential calcium leakage from the sarcoplasmic reticulum (SR) is found in certain disease conditions such as dystrophy, aging or muscle overuse. Here, we first assessed the effect of calstabin1 depletion on resting Ca²⁺ levels and transients. We found that depletion of calstabin1 with the calstabin1-dissociation compound FK506 increased the release of calcium from the SR by 14 % during tetanic stimulation (50 Hz, 300 ms) and delayed cytosolic calcium removal. However, we did not find a significant increase in resting cytosolic Ca²⁺ levels. Therefore, we tested if increased SERCA activity could counterbalance calcium leakage. By measuring the energy utilization of muscle fibers with and without FK506 treatment, we observed that FK506-treatment increased oxygen consumption by 125% compared to baseline levels. Finally, we found that pretreatment of muscle fibers with the RyR1 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 channels due to increased SERCA activity. Therefore, we suggest that RyR1 leakiness might lead to chronic metabolic stress, followed by cellular damage, and RyR1 stabilizers could potentially protect diseased muscle tissue.

Subject (DDC)

570 Biosciences, Biology

Cite This

ISO 690

BRECKNER, Anke, Magdalena GANZ, David MARCELLIN, Jens RICHTER, Nicole GERWIN, Martin RAUSCH, 2013. Effect of Calstabin1 Depletion on Calcium Transients and Energy Utilization in Muscle Fibers and Treatment Opportunities with RyR1 Stabilizers. In: PLoS one. 8(11), e81277. eISSN 1932-6203. Available under: doi: 10.1371/journal.pone.0081277

BibTex

@article{Breckner2013-11-26Effec-42245,
  year={2013},
  doi={10.1371/journal.pone.0081277},
  title={Effect of Calstabin1 Depletion on Calcium Transients and Energy Utilization in Muscle Fibers and Treatment Opportunities with RyR1 Stabilizers},
  number={11},
  volume={8},
  journal={PLoS one},
  author={Breckner, Anke and Ganz, Magdalena and Marcellin, David and Richter, Jens and Gerwin, Nicole and Rausch, Martin},
  note={Article Number: e81277}
}

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