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Related Experiment Videos

Rapamycin and FK506 reduce skeletal muscle voltage sensor expression and function.

Guillermo Avila1, Robert T Dirksen

  • 1Department of Biochemistry, Cinvestav-IPN, AP 14-740. Mexico City, DF 07000, Mexico.

Cell Calcium
|June 16, 2005
PubMed
Summary

FK506 and rapamycin impair skeletal muscle excitation-contraction coupling by reducing calcium release. These immunosuppressants decrease voltage-gated calcium release without affecting calcium stores.

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Area of Science:

  • Muscle Physiology
  • Pharmacology
  • Cellular Biology

Background:

  • FK506 and rapamycin are immunosuppressants.
  • They disrupt FK506-binding proteins (FKBPs) interaction with ryanodine receptors (RyR1).
  • RyR1 channels control Ca2+ release in skeletal muscle sarcoplasmic reticulum (SR).

Purpose of the Study:

  • Characterize short-term effects of FK506 and rapamycin on skeletal muscle excitation-contraction (EC) coupling.
  • Investigate impacts on dihydropyridine receptor (DHPR) function, resting intracellular Ca2+, and SR Ca2+ content.

Main Methods:

  • Skeletal myotubes treated with FK506 or rapamycin (20 microM for 2 h).
  • Measured voltage-gated SR Ca2+ release amplitude ((DeltaF/F)max).
  • Assessed charge movement (Qmax) and L-type Ca2+ channel conductance (Gmax).

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Main Results:

  • Both drugs reduced maximal Ca2+ release by 70-75%.
  • Maximal charge movement (Qmax) and L-type Ca2+ channel conductance (Gmax) decreased by 50%.
  • Resting myoplasmic Ca2+ and SR Ca2+ content remained unchanged.

Conclusions:

  • Impairment of EC coupling is not due to store depletion.
  • Inhibitory effects result from reduced functional sarcolemmal voltage sensors.
  • Reduced intrinsic gain of voltage-gated Ca2+ release contributes to the observed effects.