IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-58393-2.html
   My bibliography  Save this article

Muscle-specific Ryanodine receptor 1 properties underlie limb-girdle muscular dystrophy 2B/R2 progression

Author

Listed:
  • Aldo Meizoso-Huesca

    (The University of Queensland)

  • Cedric R. Lamboley

    (The University of Queensland)

  • James R. Krycer

    (QIMR Berghofer Medical Research Institute
    Queensland University of Technology)

  • Mark P. Hodson

    (QIMR Berghofer Medical Research Institute
    Queensland University of Technology
    The University of Queensland)

  • James E. Hudson

    (The University of Queensland
    QIMR Berghofer Medical Research Institute
    Queensland University of Technology)

  • Bradley S. Launikonis

    (The University of Queensland)

Abstract

Ryanodine receptor 1 Ca2+ leak is a signal in skeletal muscle, but chronic leak can underlie pathology. Here we show that in healthy male mouse, limb-girdle muscle presents higher sympathetic input, elevated ryanodine receptor 1 basal phosphorylation, Ca2+ leak and mitochondrial Ca2+ content compared to distal leg muscles. These regional differences are consistent with heat generation in resting muscle to maintain core temperature. The dysferlin-null mouse develops severe pathology in the limb-girdle but not leg muscles. Absence of dysferlin disrupts dihydropyridine receptors’ inhibitory control over ryanodine receptor 1 leak, synergistically increasing leak through the already phosphorylated channel of limb-girdle muscle. This alters Ca2+ handling and distribution leading to reactive oxygen species production prior to disease onset. With age, oxidation of Ca2+ -handling proteins in dysferlin-null limb-girdle muscle alters basal Ca2+ movements. Our results show that muscle-specific pathology in dysferlin-null mice is linked to increased ryanodine receptor 1 Ca2+ leak.

Suggested Citation

  • Aldo Meizoso-Huesca & Cedric R. Lamboley & James R. Krycer & Mark P. Hodson & James E. Hudson & Bradley S. Launikonis, 2025. "Muscle-specific Ryanodine receptor 1 properties underlie limb-girdle muscular dystrophy 2B/R2 progression," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58393-2
    DOI: 10.1038/s41467-025-58393-2
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-58393-2
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-58393-2?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Dimple Bansal & Katsuya Miyake & Steven S. Vogel & Séverine Groh & Chien-Chang Chen & Roger Williamson & Paul L. McNeil & Kevin P. Campbell, 2003. "Defective membrane repair in dysferlin-deficient muscular dystrophy," Nature, Nature, vol. 423(6936), pages 168-172, May.
    2. Nadège Zanou & Haikel Dridi & Steven Reiken & Tanes Imamura de Lima & Chris Donnelly & Umberto De Marchi & Manuele Ferrini & Jeremy Vidal & Leah Sittenfeld & Jerome N. Feige & Pablo M. Garcia-Roves & , 2021. "Acute RyR1 Ca2+ leak enhances NADH-linked mitochondrial respiratory capacity," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Hsiang-Ling Huang & Giovanna Grandinetti & Sarah M. Heissler & Krishna Chinthalapudi, 2024. "Cryo-EM structures of the membrane repair protein dysferlin," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    2. Helena Escobar & Silvia Di Francescantonio & Julia Smirnova & Robin Graf & Stefanie Müthel & Andreas Marg & Alexej Zhogov & Supriya Krishna & Eric Metzler & Mina Petkova & Oliver Daumke & Ralf Kühn & , 2025. "Gene-editing in patient and humanized-mice primary muscle stem cells rescues dysferlin expression in dysferlin-deficient muscular dystrophy," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    3. repec:plo:pone00:0003863 is not listed on IDEAS
    4. Mahtab Tavasoli & Sarah Lahire & Stanislav Sokolenko & Robyn Novorolsky & Sarah Anne Reid & Abir Lefsay & Meredith O. C. Otley & Kitipong Uaesoontrachoon & Joyce Rowsell & Sadish Srinivassane & Molly , 2022. "Mechanism of action and therapeutic route for a muscular dystrophy caused by a genetic defect in lipid metabolism," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    5. Viviane Tran & Sarah Nahlé & Amélie Robert & Inès Desanlis & Ryan Killoran & Sophie Ehresmann & Marie-Pier Thibault & David Barford & Kodi S. Ravichandran & Martin Sauvageau & Matthew J. Smith & Marie, 2022. "Biasing the conformation of ELMO2 reveals that myoblast fusion can be exploited to improve muscle regeneration," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58393-2. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.