The potential pathogenic role of disturbed Ca2+ homeostasis in Duchenne muscular dystrophy (DMD) remains a complex, unsettled issue. We used muscle fibers isolated from 3-mo-old DMDmdx rats to further investigate the case. Most DMDmdx fibers exhibited no sign of trophic or morphology distinction as compared with WT fibers and mitochondria and t-tubule membrane networks also showed no stringent discrepancy. Under voltage clamp, values for holding current were similar in the two groups, whereas values for capacitance were larger in DMDmdx fibers, suggestive of enhanced amount of t-tubule membrane. The Ca2+ current density across the channel carried by the EC coupling voltage sensor (CaV1.1) was unchanged. The maximum rate of voltage-activated sarcoplasmic reticulum (SR) Ca2+ release was reduced by 25% in the DMDmdx fibers, with no change in voltage dependency. Imaging resting Ca2+ revealed rare spontaneous local SR Ca2+ release events with no sign of elevated activity in DMDmdx fibers. Under current clamp, DMDmdx fibers generated similar trains of action potentials as WT fibers. Results suggest that reduced peak amplitude of SR Ca2+ release is an inherent feature of this DMD model, likely contributing to muscle weakness. This occurs despite a preserved amount of releasable Ca2+ and with no change in excitability, CaV1.1 channel activity, and SR Ca2+ release at rest. Although we cannot exclude that fibers from the 3-mo-old animals do not yet display a fully developed disease phenotype, results provide limited support for pathomechanistic concepts frequently associated with DMD such as membrane fragility, excessive Ca2+ entry, or enhanced SR Ca2+ leak.
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December 24 2024
Reduced voltage-activated Ca2+ release flux in muscle fibers from a rat model of Duchenne dystrophy
Jonathan Schreiber
,
Jonathan Schreiber
(Formal analysis, Investigation, Writing - review & editing)
1
University Lyon, Université Claude Bernard Lyon 1, CNRS UMR-5261, INSERM U-1315, Institut NeuroMyoGène - Pathophysiology and Genetics of Neuron and Muscle
, Lyon, France
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Ludivine Rotard
,
Ludivine Rotard
(Formal analysis, Investigation, Visualization, Writing - review & editing)
1
University Lyon, Université Claude Bernard Lyon 1, CNRS UMR-5261, INSERM U-1315, Institut NeuroMyoGène - Pathophysiology and Genetics of Neuron and Muscle
, Lyon, France
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Yves Tourneur
,
Yves Tourneur
(Formal analysis, Software)
2UFPE Department Nutrição,
Cidade Universitária
, Recife, Brazil
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Aude Lafoux
,
Aude Lafoux
(Resources)
3
Therassay Platform, CAPACITES, Nantes Université
, Nantes, France
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Christine Berthier
,
Christine Berthier
(Project administration, Supervision)
1
University Lyon, Université Claude Bernard Lyon 1, CNRS UMR-5261, INSERM U-1315, Institut NeuroMyoGène - Pathophysiology and Genetics of Neuron and Muscle
, Lyon, France
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Bruno Allard
,
Bruno Allard
(Conceptualization, Writing - review & editing)
1
University Lyon, Université Claude Bernard Lyon 1, CNRS UMR-5261, INSERM U-1315, Institut NeuroMyoGène - Pathophysiology and Genetics of Neuron and Muscle
, Lyon, France
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Corinne Huchet
,
Corinne Huchet
(Methodology, Resources, Validation, Writing - review & editing)
3
Therassay Platform, CAPACITES, Nantes Université
, Nantes, France
4Nantes Gene Therapy Laboratory,
Nantes Université, INSERM UMR TARGET 1089
, Nantes, France
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Vincent Jacquemond
(Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing)
1
University Lyon, Université Claude Bernard Lyon 1, CNRS UMR-5261, INSERM U-1315, Institut NeuroMyoGène - Pathophysiology and Genetics of Neuron and Muscle
, Lyon, France
Correspondence to Vincent Jacquemond: [email protected]
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Jonathan Schreiber
Formal analysis, Investigation, Writing - review & editing
1
University Lyon, Université Claude Bernard Lyon 1, CNRS UMR-5261, INSERM U-1315, Institut NeuroMyoGène - Pathophysiology and Genetics of Neuron and Muscle
, Lyon, France
Ludivine Rotard
Formal analysis, Investigation, Visualization, Writing - review & editing
1
University Lyon, Université Claude Bernard Lyon 1, CNRS UMR-5261, INSERM U-1315, Institut NeuroMyoGène - Pathophysiology and Genetics of Neuron and Muscle
, Lyon, France
Yves Tourneur
Formal analysis, Software
2UFPE Department Nutrição,
Cidade Universitária
, Recife, Brazil
Aude Lafoux
Resources
3
Therassay Platform, CAPACITES, Nantes Université
, Nantes, France
Christine Berthier
Project administration, Supervision
1
University Lyon, Université Claude Bernard Lyon 1, CNRS UMR-5261, INSERM U-1315, Institut NeuroMyoGène - Pathophysiology and Genetics of Neuron and Muscle
, Lyon, France
Bruno Allard
Conceptualization, Writing - review & editing
1
University Lyon, Université Claude Bernard Lyon 1, CNRS UMR-5261, INSERM U-1315, Institut NeuroMyoGène - Pathophysiology and Genetics of Neuron and Muscle
, Lyon, France
Corinne Huchet
Methodology, Resources, Validation, Writing - review & editing
3
Therassay Platform, CAPACITES, Nantes Université
, Nantes, France
4Nantes Gene Therapy Laboratory,
Nantes Université, INSERM UMR TARGET 1089
, Nantes, France
Vincent Jacquemond
Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
University Lyon, Université Claude Bernard Lyon 1, CNRS UMR-5261, INSERM U-1315, Institut NeuroMyoGène - Pathophysiology and Genetics of Neuron and Muscle
, Lyon, France
Correspondence to Vincent Jacquemond: [email protected]
Disclosures: The authors declare no competing interests exist.
Received:
April 09 2024
Revision Received:
August 14 2024
Revision Received:
November 20 2024
Accepted:
December 06 2024
Online ISSN: 1540-7748
Print ISSN: 0022-1295
Funder(s):
Centre National de la Recherche Scientifique
Funder(s):
Institut national de la santé et de la recherche médicale
Funder(s):
Université Claude Bernard - Lyon 1
Funder(s):
Institut NeuroMyoGène – Pathophysiology and Genetics of Neuron and Muscle
- Award Id(s): CNRS UMR5261- INSERM U1315
Funder(s):
Association Française contre les Myopathies
- Award Id(s): 4.1.1
© 2024 Schreiber et al.
2024
Schreiber et al.
This article is distributed under the terms as described at https://rupress.org/pages/terms102024/.
J Gen Physiol (2025) 157 (2): e202413588.
Article history
Received:
April 09 2024
Revision Received:
August 14 2024
Revision Received:
November 20 2024
Accepted:
December 06 2024
Citation
Jonathan Schreiber, Ludivine Rotard, Yves Tourneur, Aude Lafoux, Christine Berthier, Bruno Allard, Corinne Huchet, Vincent Jacquemond; Reduced voltage-activated Ca2+ release flux in muscle fibers from a rat model of Duchenne dystrophy. J Gen Physiol 3 March 2025; 157 (2): e202413588. doi: https://doi.org/10.1085/jgp.202413588
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