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Hum Mol Genet. 2015 Dec 1;24(23):6580-7. doi: 10.1093/hmg/ddv361. Epub 2015 Sep 14.

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

Author information

1
Department of Physiology and Pharmacology.
2
Department of Laboratory Medicine.
3
Center for Inherited Metabolic Disease (CMMS), Karolinska University Hospital, Stockholm, Sweden.
4
Department of Molecular Medicine and Surgery, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden and Center for Inherited Metabolic Disease (CMMS), Karolinska University Hospital, Stockholm, Sweden.
5
Department of Laboratory Medicine, Center for Inherited Metabolic Disease (CMMS), Karolinska University Hospital, Stockholm, Sweden.
6
Department of Laboratory Medicine, Center for Inherited Metabolic Disease (CMMS), Karolinska University Hospital, Stockholm, Sweden anna.wredenberg@ki.se hakan.westerblad@ki.se.
7
Department of Physiology and Pharmacology, anna.wredenberg@ki.se hakan.westerblad@ki.se.

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.

PMID:
26374844
PMCID:
PMC4634369
DOI:
10.1093/hmg/ddv361
[Indexed for MEDLINE]
Free PMC Article

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