Abstract | KEY POINTS:
Dysferlin, the protein missing in limb girdle muscular dystrophy 2B and Miyoshi myopathy, concentrates in transverse tubules of skeletal muscle, where it stabilizes voltage-induced Ca2+ transients against loss after osmotic shock injury (OSI). Local expression of dysferlin in dysferlin-null myofibres increases transient amplitude to control levels and protects them from loss after OSI. Inhibitors of ryanodine receptors ( RyR1) and L-type Ca2+ channels protect voltage-induced Ca2+ transients from loss; thus both proteins play a role in injury in dysferlin's absence. Effects of Ca2+ -free medium and S107, which inhibits SR Ca2+ leak, suggest the SR as the primary source of Ca2+ responsible for the loss of the Ca2+ transient upon injury. Ca2+ waves were induced by OSI and suppressed by exogenous dysferlin. We conclude that dysferlin prevents injury-induced SR Ca2+ leak. ABSTRACT:
Dysferlin concentrates in the transverse tubules of skeletal muscle and stabilizes Ca2+ transients when muscle fibres are subjected to osmotic shock injury (OSI). We show here that voltage-induced Ca2+ transients elicited in dysferlin-null A/J myofibres were smaller than control A/WySnJ fibres. Regional expression of Venus- dysferlin chimeras in A/J fibres restored the full amplitude of the Ca2+ transients and protected against OSI. We also show that drugs that target ryanodine receptors ( RyR1: dantrolene, tetracaine, S107) and L-type Ca2+ channels (LTCCs: nifedipine, verapamil, diltiazem) prevented the decrease in Ca2+ transients in A/J fibres following OSI. Diltiazem specifically increased transients by ∼20% in uninjured A/J fibres, restoring them to control values. The fact that both RyR1s and LTCCs were involved in OSI-induced damage suggests that damage is mediated by increased Ca2+ leak from the sarcoplasmic reticulum (SR) through the RyR1. Congruent with this, injured A/J fibres produced Ca2+ sparks and Ca2+ waves. S107 (a stabilizer of RyR1- FK506 binding protein coupling that reduces Ca2+ leak) or local expression of Venus- dysferlin prevented OSI-induced Ca2+ waves. Our data suggest that dysferlin modulates SR Ca2+ release in skeletal muscle, and that in its absence OSI causes increased RyR1-mediated Ca2+ leak from the SR into the cytoplasm.
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Authors | Valeriy Lukyanenko, Joaquin M Muriel, Robert J Bloch |
Journal | The Journal of physiology
(J Physiol)
Vol. 595
Issue 15
Pg. 5191-5207
(08 01 2017)
ISSN: 1469-7793 [Electronic] England |
PMID | 28568606
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society. |
Chemical References |
- Calcium Channels, L-Type
- Dysf protein, mouse
- Dysferlin
- Ryanodine Receptor Calcium Release Channel
- S-107 compound
- Thiazepines
- ryanodine receptor 1, mouse
- Calcium
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Topics |
- Animals
- Calcium
(physiology)
- Calcium Channels, L-Type
(physiology)
- Dysferlin
(genetics, physiology)
- Mice, Knockout
- Muscle Fibers, Skeletal
(physiology)
- Osmotic Pressure
(physiology)
- Ryanodine Receptor Calcium Release Channel
(physiology)
- Sarcoplasmic Reticulum
(physiology)
- Thiazepines
(pharmacology)
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