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Updated: Aug 1, 2025
14:02
Ex Vivo Assessment of Contractility, Fatigability and Alternans in Isolated Skeletal Muscles
Published on: November 1, 2012
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Feedback contributions to excitation-contraction coupling in native functioning striated muscle
Samantha C Salvage1, Angela F Dulhunty2, Kamalan Jeevaratnam3
1Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, UK.
Summary
Sarcoplasmic reticulum calcium release negatively impacts sodium channel function in muscle. Inhibiting ryanodine receptors or calcium pumps restores normal sodium currents, suggesting a feedback mechanism in muscle excitation.
Area of Science:
- Muscle physiology and biophysics
- Cardiovascular research
- Molecular and cellular biology
Background:
- Excitation-contraction coupling in skeletal and cardiac muscle relies on sodium channel (Nav1.4/Nav1.5) activity.
- The interplay between sodium channel function and sarcoplasmic reticulum (SR) calcium release is not fully understood.
- Previous studies suggest potential feedback mechanisms regulating muscle excitability.
Purpose of the Study:
- To investigate the feedback effects of SR calcium release on Nav1.4/Nav1.5 channel function in native muscle.
- To explore the role of specific structural domains and mutations in Nav1.4/Nav1.5 in clinical conditions.
- To examine the impact of altered calcium handling on muscle action potential generation and propagation.
Main Methods:
- Utilized finite-element modeling to predict junctional SR calcium domains.
- Employed loose-patch clamp electrophysiology on murine skeletal muscle fibers and cardiomyocytes.
- Investigated the effects of SR calcium release activators (e.g., 8-(4-chlorophenylthio)adenosine-3',5'-cyclic monophosphate, caffeine) and inhibitors (e.g., dantrolene, cyclopiazonic acid).
- Examined experimental models of cardiac arrhythmias (RyR2-P2328S) and metabolic deficiency (Pgc1β-/-).
Main Results:
- SR calcium release reduced Na+ currents (INa) in muscle fibers and cardiomyocytes, an effect abrogated by RyR inhibition.
- RyR inhibition and Ca2+-ATPase inhibition increased INa.
- Experimental models with abnormal calcium handling exhibited reduced INa, which was rescued by RyR blockade.
- Hydroxychloroquine challenge demonstrated that action potential prolongation, via modified calcium transients, slowed action potential upstrokes and conduction velocities.
Conclusions:
- SR calcium release exerts a feedback inhibition on Nav1.4/Nav1.5 channel activity in native muscle.
- Mutations in Nav1.4/Nav1.5 binding sites are linked to specific clinical conditions.
- Altered calcium dynamics can lead to pro-arrhythmic effects by slowing action potential conduction.
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