Functional Characterization of an Immortalized Human Muscle Cell Line Carrying the Heterozygous RyR1 p.T4288_A4290dup Associated With Rhabdomyolysis.
8 affiliations
- 1Departments of Neurology and Biomedicine Basel University Hospital Basel Switzerland unispital-basel.ch.
- 2Department of Anesthesiology and Critical Care Hiroshima University Hospital Hiroshima Japan hiroshima-u.ac.jp.
- 3Dubowitz Neuromuscular Center Developmental Neurosciences Research and Teaching Department Great Ormond Street Institute of Child Health University College London London UK ucl.ac.uk.
- 4NIHR Great Ormond Street Hospital Biomedical Research Center London UK.
- 5Genetic Therapy Accelerator Center Institute of Neurology and UCL Great Ormond Street Institute of Child Health London UK.
- 6Institut de Myologie Centre de Recherche en Myologie Université Sorbonne Inserm Paris France inserm.fr.
- 7Proteomics Core Facility Biozentrum University of Basel Basel Switzerland unibas.ch.
- 8Department of Life Sciences and Biotechnology University of Ferrara Ferrara Italy unife.it.
Abstract
The ryanodine receptor 1 plays an essential role in skeletal muscle by releasing the calcium necessary for contraction from the sarcoplasmic reticulum and mutations in RYR1, the gene encoding the ryanodine receptor 1 are associated with a variety of neuromuscular phenotypes, ranging from core myopathies and centronuclear myopathy to the pharmacogenetic disorder malignant hyperthermia. The muscle phenotype of the patient mainly depends on whether the mutations are dominant or recessive and on their location within the gene. Gain of function RYR1 mutations usually affect the biophysical properties of the calcium channel and are associated with malignant hyperthermia susceptibility trait with or without a myopathy. From a functional point of view, these mutations render the calcium channel oversensitive thereby facilitating its opening and allowing more calcium to be released from the sarcoplasmic reticulum. More recently exertional rhabdomyolysis has been observed in particularly athletic individuals who also carry gain of function RYR1 variants, but so far no functional studies have been performed investigating if and how such variants affect ryanodine receptor 1 calcium channels. In the present report we used an immortalized muscle cell line from an individual with exertional rhabdomyolysis carrying the heterozygous RyR1 duplication p.T4288_A4290dup in exon 91 and show that the presence of this variant is associated with morphometric changes in myotubes, enhanced myotube maturation and enhanced calcium release following membrane depolarization and pharmacological RyR1 activation. The enhanced calcium release would lead to more efficient muscle contraction but would also result in increased activation of SERCA pumps, more ATP consumption and increased enzymatic activity of the calcium dependent protease calpain 3. We hypothesize that these events are potentially the underlying (co)causes of exercise-induced rhabdomyolysis in individuals carrying this RyR1 variant.
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BibTeX
@article{jin2026functional,
title = {{Functional Characterization of an Immortalized Human Muscle Cell Line Carrying the Heterozygous RyR1 p.T4288_A4290dup Associated With Rhabdomyolysis.}},
author = {Wen Jin and Irem Huriye Ceren and Kenshiro Kido and Alexis Ruiz and Teresa Ianiri and Anna Sarkozy and Francesco Muntoni and Kamel Mamchaoui and Katarzyna Buczak and Francesco Zorzato and Susan Treves},
journal = {Human mutation},
year = {2026},
month = oct,
doi = {10.1155/humu/8852225},
url = {https://europepmc.org/article/MED/42948550},
note = {CC BY},
}
RIS
TY - JOUR
TI - Functional Characterization of an Immortalized Human Muscle Cell Line Carrying the Heterozygous RyR1 p.T4288_A4290dup Associated With Rhabdomyolysis.
AU - Wen Jin
AU - Irem Huriye Ceren
AU - Kenshiro Kido
AU - Alexis Ruiz
AU - Teresa Ianiri
AU - Anna Sarkozy
AU - Francesco Muntoni
AU - Kamel Mamchaoui
AU - Katarzyna Buczak
AU - Francesco Zorzato
AU - Susan Treves
PY - 2026
DA - 2026/10/27
JO - Human mutation
DO - 10.1155/humu/8852225
UR - https://europepmc.org/article/MED/42948550
AB - The ryanodine receptor 1 plays an essential role in skeletal muscle by releasing the calcium necessary for contraction from the sarcoplasmic reticulum and mutations in RYR1, the gene encoding the ryanodine receptor 1 are associated with a variety of neuromuscular phenotypes, ranging from core myopathies and centronuclear myopathy to the pharmacogenetic disorder malignant hyperthermia. The muscle phenotype of the patient mainly depends on whether the mutations are dominant or recessive and on their location within the gene. Gain of function RYR1 mutations usually affect the biophysical properties of the calcium channel and are associated with malignant hyperthermia susceptibility trait with or without a myopathy. From a functional point of view, these mutations render the calcium channel oversensitive thereby facilitating its opening and allowing more calcium to be released from the sarcoplasmic reticulum. More recently exertional rhabdomyolysis has been observed in particularly athletic individuals who also carry gain of function RYR1 variants, but so far no functional studies have been performed investigating if and how such variants affect ryanodine receptor 1 calcium channels. In the present report we used an immortalized muscle cell line from an individual with exertional rhabdomyolysis carrying the heterozygous RyR1 duplication p.T4288_A4290dup in exon 91 and show that the presence of this variant is associated with morphometric changes in myotubes, enhanced myotube maturation and enhanced calcium release following membrane depolarization and pharmacological RyR1 activation. The enhanced calcium release would lead to more efficient muscle contraction but would also result in increased activation of SERCA pumps, more ATP consumption and increased enzymatic activity of the calcium dependent protease calpain 3. We hypothesize that these events are potentially the underlying (co)causes of exercise-induced rhabdomyolysis in individuals carrying this RyR1 variant.
SN - 1059-7794
SN - 1098-1004
ER -