Role of oxidation of excitation-contraction coupling machinery in age-dependent loss of muscle function in C. elegans

  1. Haikel Dridi
  2. Frances Forrester
  3. Alisa Umanskaya
  4. Wenjun Xie
  5. Steven Reiken
  6. Alain Lacampagne
  7. Andrew Marks  Is a corresponding author
  1. Columbia University Medical Center, United States
  2. Montpellier University, INSERM, CNRS, France

Abstract

Age-dependent loss of body wall muscle function and impaired locomotion occur within 2 weeks in C. elegans; however, the underlying mechanism has not been fully elucidated. In humans, age-dependent loss of muscle function occurs at about 80 years of age and has been linked to dysfunction of ryanodine receptor (RyR)/intracellular calcium (Ca2+) release channels on the sarcoplasmic reticulum (SR). Mammalian skeletal muscle RyR1 channels undergo age-related remodeling due to oxidative overload, leading to loss of the stabilizing subunit calstabin1 (FKBP12) from the channel macromolecular complex. This destabilizes the closed state of the channel resulting in intracellular Ca2+ leak, reduced muscle function, and impaired exercise capacity. We now show that the C. elegans RyR homolog, UNC-68, exhibits a remarkable degree of evolutionary conservation with mammalian RyR channels and similar age-dependent dysfunction. Like RyR1 in mammals UNC-68 encodes a protein that comprises a macromolecular complex which includes the calstabin1 homolog FKB-2 and is immunoreactive with antibodies raised against the RyR1 complex. Further, as in aged mammals, UNC-68 is oxidized and depleted of FKB-2 in an age-dependent manner, resulting in 'leaky' channels, depleted SR Ca2+ stores, reduced body wall muscle Ca2+ transients, and age-dependent muscle weakness. FKB-2 (ok3007)-deficient worms exhibit reduced exercise capacity. Pharmacologically induced oxidization of UNC-68 and depletion of FKB-2 from the channel independently caused reduced body wall muscle Ca2+ transients. Preventing FKB-2 depletion from the UNC-68 macromolecular complex using the Rycal drug S107 improved muscle Ca2+ transients and function. Taken together, these data suggest that UNC-68 oxidation plays a role in age-dependent loss of muscle function. Remarkably, this age-dependent loss of muscle function induced by oxidative overload, which takes ~2 years in mice and ~80 years in humans, occurs in less than 2-3 weeks in C. elegans, suggesting that reduced antioxidant capacity may contribute to the differences in life span amongst species.

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All data are described/available in the manuscript

Article and author information

Author details

  1. Haikel Dridi

    Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9533-7367
  2. Frances Forrester

    Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, United States
    Competing interests
    No competing interests declared.
  3. Alisa Umanskaya

    Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, United States
    Competing interests
    No competing interests declared.
  4. Wenjun Xie

    Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, United States
    Competing interests
    No competing interests declared.
  5. Steven Reiken

    Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, United States
    Competing interests
    No competing interests declared.
  6. Alain Lacampagne

    U1046, Montpellier University, INSERM, CNRS, Montpellier, France
    Competing interests
    No competing interests declared.
  7. Andrew Marks

    Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, United States
    For correspondence
    arm42@cumc.columbia.edu
    Competing interests
    Andrew Marks, owns stock in ARMGO, Inc. a company developing compounds targeting RyR and has patents on Rycals.US 2014/0378437, and US 7,718,644..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8057-1502

Funding

National Heart, Lung, and Blood Institute (R01HL145473)

  • Andrew Marks

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK118240)

  • Andrew Marks

National Heart, Lung, and Blood Institute (R01HL142903)

  • Andrew Marks

National Heart, Lung, and Blood Institute (R01HL061503)

  • Andrew Marks

National Heart, Lung, and Blood Institute (R01HL140934)

  • Andrew Marks

National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR070194)

  • Andrew Marks

National Heart, Lung, and Blood Institute (T32HL120826)

  • Andrew Marks

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2022, Dridi et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Haikel Dridi
  2. Frances Forrester
  3. Alisa Umanskaya
  4. Wenjun Xie
  5. Steven Reiken
  6. Alain Lacampagne
  7. Andrew Marks
(2022)
Role of oxidation of excitation-contraction coupling machinery in age-dependent loss of muscle function in C. elegans
eLife 11:e75529.
https://doi.org/10.7554/eLife.75529

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https://doi.org/10.7554/eLife.75529

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