Ca2+ Signaling in HEK-293 and Skeletal Muscle Cells Expressing Recombinant Ryanodine Receptors Harboring Malignant Hyperthermia and Central Core Disease Mutations

Brini, Marisa; Manni, Sabrina; Pierobon, Nicola; Du, Guo Guang; Sharma, Parveen; MacLennan, David H.; Carafoli, Ernesto

doi:10.1074/jbc.m410421200

Cited by 52 publications

(46 citation statements)

References 36 publications

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“…Over 300 mutations are identified in human RyR1, with most mutations being found in three separate regions (30). RyR1 mutations have disparate effects on Ca 2ϩ release, which differentially influences energy homeostasis, muscle phenotype, and viability (5). While the most severe phenotype is associated with mutations in the pore of the Ca 2ϩ release channel, the majority of mutations are mapped to interdomain and intersubunit interfaces (8).…”

Section: Discussionmentioning

confidence: 99%

Fiber hypertrophy and increased oxidative capacity can occur simultaneously in pig glycolytic skeletal muscle

Scheffler

Park

Kasten

et al. 2014

American Journal of Physiology-Cell Physiology

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An inverse relationship between skeletal muscle fiber cross-sectional area (CSA) and oxidative capacity suggests that muscle fibers hypertrophy at the expense of oxidative capacity. Therefore, our objective was to utilize pigs possessing mutations associated with increased oxidative capacity [AMP-activated protein kinase (AMPKγ3(R200Q))] or fiber hypertrophy [ryanodine receptor 1 (RyR1(R615C))] to determine if these events occur in parallel. Longissimus muscle was collected from wild-type (control), AMPKγ3(R200Q), RyR1(R615C), and AMPKγ3(R200Q)-RyR1(R615C) pigs. Regardless of AMPK genotype, RyR(R615C) increased fiber CSA by 35%. In contrast, AMPKγ3(R200Q) pig muscle exhibited greater citrate synthase and β-hydroxyacyl CoA dehydrogenase activity. Isolated mitochondria from AMPKγ3(R200Q) muscle had greater maximal, ADP-stimulated oxygen consumption rate. Additionally, AMPKγ3(R200Q) muscle contained more (∼50%) of the mitochondrial proteins succinate dehydrogenase and cytochrome c oxidase and more mitochondrial DNA. Surprisingly, RyR1(R615C) increased mitochondrial proteins and DNA, but this was not associated with improved oxidative capacity, suggesting that altered energy metabolism in RyR1(R615C) muscle influences mitochondrial proliferation and protein turnover. Thus pigs that possess both AMPKγ3(R200Q) and RyR(R615C) exhibit increased muscle fiber CSA as well as greater oxidative capacity. Together, our findings support the notion that hypertrophy and enhanced oxidative capacity can occur simultaneously in skeletal muscle and suggest that the signaling mechanisms controlling these events are independently regulated.

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Section: Discussionmentioning

confidence: 99%

Fiber hypertrophy and increased oxidative capacity can occur simultaneously in pig glycolytic skeletal muscle

Scheffler

Park

Kasten

et al. 2014

American Journal of Physiology-Cell Physiology

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“…For example, patients with malignant hyperthermia (MH) and central core disease (CCD) (Rosenberg et al, 2007;Treves et al, 2008) often show mutations in the RyR1, which leads to altered [Ca 2+ ] c and [Ca 2+ ] m transients (Brini et al, 2005). In the RyR1(Y522S) knock-in mouse model of MH, RyR1(Y522S) undergoes redox modifications due to elevated ROS and becomes leaky.…”

Section: Ros As Regulatory Signaling Factors In Cardiac and Skeletal mentioning

confidence: 99%

Interactions between sarco-endoplasmic reticulum and mitochondria in cardiac and skeletal muscle – pivotal roles in Ca2+ and reactive oxygen species signaling

Eisner

Csordás

Hajnóczky

2013

Journal of Cell Science

186

174

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SummaryMitochondria are strategically and dynamically positioned in the cell to spatially coordinate ATP production with energy needs and to allow the local exchange of material with other organelles. Interactions of mitochondria with the sarco-endoplasmic reticulum (SR/ER) have been receiving much attention owing to emerging evidence on the role these sites have in cell signaling, dynamics and biosynthetic pathways. One of the most important physiological and pathophysiological paradigms for SR/ER-mitochondria interactions is in cardiac and skeletal muscle. The contractile activity of these tissues has to be matched by mitochondrial ATP generation that is achieved, at least in part, by propagation of Ca 2+ signals from SR to mitochondria. However, the muscle has a highly ordered structure, providing only limited opportunity for mitochondrial dynamics and interorganellar interactions. This Commentary focuses on the latest advances in the structure, function and disease relevance of the communication between SR/ER and mitochondria in muscle. In particular, we discuss the recent demonstration of SR/ER-mitochondria tethers that are formed by multiple proteins, and local Ca 2+ transfer between SR/ER and mitochondria.

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“…The p.Cys4664Arg mutation is located at the C-terminal region of the protein in the M6 transmembrane segment [Zorzato et al, 1990]. Other mutations at the C-terminus of RYR1 and associated with the CCD phenotype have been reported to lead to channels that are non-or hypo-reactive to chemical stimulation [Brini et al, 2005;Ducreux et al, 2004;Tilgen et al, 2001;Lynch et al, 1999]. In contrast, the p.Thr4826Ile mutation, associated to the MHS phenotype, was reported to have a higher 4-CmC and caffeine sensitivity compared to the wild-type RYR1 in transfected human myotubes [Yang et al 2003].…”

Section: Discussionmentioning

confidence: 99%

Functional characterization of ryanodine receptor (RYR1) sequence variants using a metabolic assay in immortalized B-lymphocytes

et al. 2009

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Mutations in the RYR1 gene are linked to malignant hyperthermia (MH), central core disease and multi-minicore disease. We screened by DHPLC the RYR1 gene in 24 subjects for mutations, and characterized functional alterations caused by some RYR1 variants. Three novel sequence variants and twenty novel polymorphisms were identified. Immortalized lymphoblastoid cell lines from patients with RYR1 variants and from controls were stimulated with 4-chloro-mcresol (4-CmC) and the rate of extracellular acidification was recorded. We demonstrate that the increased acidification rate of lymphoblastoid cells in response to 4-CmC is mainly due to RYR1 activation. Cells expressing RYR1 variants in the N-terminal and in the central region of the protein (p.Arg530His, p.Arg2163Pro, p.Asn2342Ser, p.Glu2371Gly and p.Arg2454His) displayed higher activity compared with controls; this could account for the MH-susceptible phenotype. Cell lines harboring RYR1P Cys4664Arg P were significantly less activated by 4-CmC. This result indicates that the p.Cys4664Arg variant causes a leaky channel and depletion of intracellular stores. The functional changes detected corroborate the variants analyzed as disease-causing alterations and the acidification rate measurements as a means to monitor CaP 2+ P-induced metabolic changes in cells harboring mutant RYR1 channels.

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Ca2+ Signaling in HEK-293 and Skeletal Muscle Cells Expressing Recombinant Ryanodine Receptors Harboring Malignant Hyperthermia and Central Core Disease Mutations

Cited by 52 publications

References 36 publications

Fiber hypertrophy and increased oxidative capacity can occur simultaneously in pig glycolytic skeletal muscle

Fiber hypertrophy and increased oxidative capacity can occur simultaneously in pig glycolytic skeletal muscle

Interactions between sarco-endoplasmic reticulum and mitochondria in cardiac and skeletal muscle – pivotal roles in Ca2+ and reactive oxygen species signaling

Functional characterization of ryanodine receptor (RYR1) sequence variants using a metabolic assay in immortalized B-lymphocytes

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