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Article

Alisporivir Improves Mitochondrial Function in Skeletal Muscle of mdx Mice but Suppresses Mitochondrial Dynamics and Biogenesis

1
Department of Biochemistry, Cell Biology and Microbiology, Mari State University, 424001 Yoshkar-Ola, Russia
2
Laboratory of Mitochondrial Transport, Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, 142290 Pushchino, Russia
*
Author to whom correspondence should be addressed.
Academic Editors: Anna Atlante and Daniela Valenti
Int. J. Mol. Sci. 2021, 22(18), 9780; https://doi.org/10.3390/ijms22189780
Received: 9 August 2021 / Revised: 5 September 2021 / Accepted: 8 September 2021 / Published: 10 September 2021
Mitigation of calcium-dependent destruction of skeletal muscle mitochondria is considered as a promising adjunctive therapy in Duchenne muscular dystrophy (DMD). In this work, we study the effect of intraperitoneal administration of a non-immunosuppressive inhibitor of calcium-dependent mitochondrial permeability transition (MPT) pore alisporivir on the state of skeletal muscles and the functioning of mitochondria in dystrophin-deficient mdx mice. We show that treatment with alisporivir reduces inflammation and improves muscle function in mdx mice. These effects of alisporivir were associated with an improvement in the ultrastructure of mitochondria, normalization of respiration and oxidative phosphorylation, and a decrease in lipid peroxidation, due to suppression of MPT pore opening and an improvement in calcium homeostasis. The action of alisporivir was associated with suppression of the activity of cyclophilin D and a decrease in its expression in skeletal muscles. This was observed in both mdx mice and wild-type animals. At the same time, alisporivir suppressed mitochondrial biogenesis, assessed by the expression of Ppargc1a, and altered the dynamics of organelles, inhibiting both DRP1-mediated fission and MFN2-associated fusion of mitochondria. The article discusses the effects of alisporivir administration and cyclophilin D inhibition on mitochondrial reprogramming and networking in DMD and the consequences of this therapy on skeletal muscle health. View Full-Text
Keywords: Duchenne muscular dystrophy; skeletal muscle; alisporivir; Debio-025; mitochondria; cyclophilin D; mitochondrial permeability transition Duchenne muscular dystrophy; skeletal muscle; alisporivir; Debio-025; mitochondria; cyclophilin D; mitochondrial permeability transition
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MDPI and ACS Style

Dubinin, M.V.; Starinets, V.S.; Talanov, E.Y.; Mikheeva, I.B.; Belosludtseva, N.V.; Belosludtsev, K.N. Alisporivir Improves Mitochondrial Function in Skeletal Muscle of mdx Mice but Suppresses Mitochondrial Dynamics and Biogenesis. Int. J. Mol. Sci. 2021, 22, 9780. https://doi.org/10.3390/ijms22189780

AMA Style

Dubinin MV, Starinets VS, Talanov EY, Mikheeva IB, Belosludtseva NV, Belosludtsev KN. Alisporivir Improves Mitochondrial Function in Skeletal Muscle of mdx Mice but Suppresses Mitochondrial Dynamics and Biogenesis. International Journal of Molecular Sciences. 2021; 22(18):9780. https://doi.org/10.3390/ijms22189780

Chicago/Turabian Style

Dubinin, Mikhail V., Vlada S. Starinets, Eugeny Y. Talanov, Irina B. Mikheeva, Natalia V. Belosludtseva, and Konstantin N. Belosludtsev. 2021. "Alisporivir Improves Mitochondrial Function in Skeletal Muscle of mdx Mice but Suppresses Mitochondrial Dynamics and Biogenesis" International Journal of Molecular Sciences 22, no. 18: 9780. https://doi.org/10.3390/ijms22189780

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