Cyclosporine A Delays the Terminal Disease Stage in the Tfam KO Mitochondrial Myopathy Mouse Model Without Improving Mitochondrial Energy Production.

Autor: Chatel B; Aix-Marseille Univ, CNRS, CRMBM, Marseille, France., Varlet I; Aix-Marseille Univ, CNRS, CRMBM, Marseille, France., Ogier AC; Aix Marseille Univ, Université de Toulon, CNRS, Lis, Marseille, France., Pecchi E; Aix-Marseille Univ, CNRS, CRMBM, Marseille, France., Bernard M; Aix-Marseille Univ, CNRS, CRMBM, Marseille, France., Gondin J; Institut NeuroMyoGène, Unité Physiopathologie et Génétique du Neurone et du Muscle, UMR CNRS 5261-INSERM U1315, Université Claude Bernard Lyon 1, Lyon, France., Westerblad H; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden., Bendahan D; Aix-Marseille Univ, CNRS, CRMBM, Marseille, France., Gineste C; Aix-Marseille Univ, CNRS, CRMBM, Marseille, France.
Jazyk: angličtina
Zdroj: Muscle & nerve [Muscle Nerve] 2024 Dec 23. Date of Electronic Publication: 2024 Dec 23.
DOI: 10.1002/mus.28315
Abstrakt: Introduction and Aims: Mitochondrial myopathies are rare genetic disorders for which no effective treatment exists. We previously showed that the pharmacological cyclophilin inhibitor cyclosporine A (CsA) extends the lifespan of fast-twitch skeletal muscle-specific mitochondrial transcription factor A knockout (Tfam KO) mice, lacking the ability to transcribe mitochondrial DNA and displaying lethal mitochondrial myopathy. Our present aim was to assess whether the positive effect of CsA was associated with improved in vivo mitochondrial energy production.
Methods: Mice were treated with CsA for 4 weeks, beginning at 12 weeks (i.e., before the terminal disease phase). Hindlimb plantar flexor muscles were fatigued by 80 contractions (40 Hz, 1.5 s on, 6 s off) while measuring force and energy metabolism using phosphorus-31 magnetic resonance spectroscopy.
Results: Force decreased at similar rates in Tfam KO mice with and without the CsA treatment, reaching 50% of the baseline value after ~14 ± 1 contractions, which was faster than in control mice (25 ± 1 contractions). Phosphocreatine (PCr) decreased to ~10% of the control concentration in Tfam KO mice, independent of the treatment, which was larger than the ~20% observed in control mice. The time constant of PCr recovery was higher in untreated Tfam KO than that in control muscle (+100%) and similar in untreated and CsA-treated Tfam KO mice.
Discussion: The results do not support improved mitochondrial energy production as a mechanism underlying the prolonged lifespan of Tfam KO mitochondrial myopathy mice treated with CsA. Thus, other mechanisms must be involved, such as the previously observed CsA-mediated protection against excessive mitochondrial Ca 2+ accumulation.
(© 2024 The Author(s). Muscle & Nerve published by Wiley Periodicals LLC.)
Databáze: MEDLINE
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