Ca2+-induced sarcoplasmic reticulum Ca2+ release in myotubularin-deficient muscle fibers. (June 2019)

• Record Type: Journal Article
• Authors: Kutchukian, Candice; Szentesi, Peter; Allard, Bruno; Buj-Bello, Ana; Csernoch, Laszlo; Jacquemond, Vincent
• Is Part Of: Cell calcium. Volume 80(2019)
• Page Start: 91
• Page End: 100
• Publication Date: 2019-06
• Subjects: CaV1.1 α1 subunit of the dihydropyridine receptor -- CNM centronuclear myopathy -- FDB flexor digitorum brevis -- EC excitation-contraction -- KO knock-out -- MTM1 myotubularin -- RYR1 type 1 ryanodine receptor -- SR sarcoplasmic reticulum -- WT wild-type; Skeletal muscle -- Ryanodine receptor -- Sarcoplasmic reticulum Ca2+ release -- Myotubular myopathy; Calcium -- Metabolism -- Periodicals; Vertebrates -- Physiology -- Periodicals; Calcium -- Physiological effect -- Periodicals; Cell physiology -- Periodicals; Calcium in the body -- Periodicals; 572.516
• DOI: 10.1016/j.ceca.2019.04.004
• Languages: English
• ISSNs: 0143-4160

Abstract

Graphical abstract: Highlights: Myotubular myopathy is due to genetic deficiency in the phosphatase myotubularin (MTM1). In healthy muscle, Ca 2+ release through ryanodine receptors is under the exclusive control of plasma membrane excitation. Conversely, we found that MTM1-deficient muscle fibers exhibit Ca 2+ release from Ca 2+ -activated ryanodine receptors. Ca 2+ -induced Ca 2+ release at rest and during activation contributes to the disease phenotype. Abstract: Skeletal muscle deficiency in the 3-phosphoinositide (PtdIns P ) phosphatase myotubularin (MTM1) causes myotubular myopathy which is associated with severe depression of voltage-activated sarcoplasmic reticulum Ca 2+ release through ryanodine receptors. In the present study we aimed at further understanding how Ca 2+ release is altered in MTM1-deficient muscle fibers, at rest and during activation. While in wild-type muscle fibers, SR Ca 2+ release exhibits fast stereotyped kinetics of activation and decay throughout the voltage range of activation, Ca 2+ release in MTM1-deficient muscle fibers exhibits slow and unconventional kinetics at intermediate voltages, suggestive of partial loss of the normal control of ryanodine receptor Ca 2+ channel activity. In addition, the diseased muscle fibers at rest exhibit spontaneous elementary Ca 2+ release events at a frequency 30 times greater than that of control fibers. Eighty percent of the events have spatiotemporal properties of archetypal Ca 2+ sparks while the rest take either the form of lower amplitude, longer duration Ca 2+ release events or of a combination thereof. The events occur at preferred locations in the fibers, indicating spatially uneven distribution of the parameters determining spontaneous ryanodine receptor 1 opening. Spatially large Ca 2+ release sources were obviously involved in some of these events, suggesting that opening of ryanodine receptors in one cluster can activate opening of ryanodine receptors in a neighboring one. Overall results demonstrate that opening of Ca 2+ -activated ryanodine receptors is promoted both at rest and during excitation-contraction coupling in MTM1-deficient muscle fibers. Because access to this activation mode is denied to ryanodine receptors in healthy skeletal muscle, this may play an important role in the associated disease situation.