Cyclophilin D, a target for counteracting skeletal muscle dysfunction in mitochondrial myopathy.

Abstract

Muscle weakness and exercise intolerance are hallmark symptoms in mitochondrial disorders. Little is known about the mechanisms leading to impaired skeletal muscle function and ultimately muscle weakness in these patients. In a mouse model of lethal mitochondrial myopathy, the muscle-specific Tfam knock-out (KO) mouse, we previously demonstrated an excessive mitochondrial Ca(2+) uptake in isolated muscle fibers that could be inhibited by the cyclophilin D (CypD) inhibitor, cyclosporine A (CsA). Here we show that the Tfam KO mice have increased CypD levels, and we demonstrate that this increase is a common feature in patients with mitochondrial myopathy. We tested the effect of CsA treatment on Tfam KO mice during the transition from a mild to terminal myopathy. CsA treatment counteracted the development of muscle weakness and improved muscle fiber Ca(2+) handling. Importantly, CsA treatment prolonged the lifespan of these muscle-specific Tfam KO mice. These results demonstrate that CsA treatment is an efficient therapeutic strategy to slow the development of severe mitochondrial myopathy.

• Authors: Charlotte Gineste, Andres Hernandez, Niklas Ivarsson, Arthur J Cheng, Karin Naess, Rolf Wibom, Nicole Lesko, Helene Bruhn, Anna Wedell, Christoph Freyer, Shi-Jin Zhang, Mattias Carlström, Johanna T Lanner, Daniel C Andersson, Joseph D Bruton, Anna Wredenberg, Håkan Westerblad
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 24 Issue 23 Pg. 6580-7 (Dec 01 2015) ISSN: 1460-2083 [Electronic] England
• PMID: 26374844 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Peptidyl-Prolyl Isomerase F
• DNA, Mitochondrial
• PPIF protein, mouse
• Cyclosporine
• Cyclophilins
• Calcium

Topics

• Animals
• Calcium (metabolism)
• Peptidyl-Prolyl Isomerase F
• Cyclophilins (antagonists & inhibitors, drug effects, genetics)
• Cyclosporine (therapeutic use)
• DNA, Mitochondrial
• Disease Models, Animal
• Gene Expression Regulation
• Humans
• Mice
• Mice, Knockout
• Mitochondria (drug effects, metabolism)
• Mitochondrial Myopathies (drug therapy, genetics, metabolism)
• Muscle, Skeletal (drug effects, metabolism)
• Mutation