title: 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.affiliation: Department of Physiology and Pharmacology.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Gineste
authors.affiliation: Department of Physiology and Pharmacology.
authors.forename: Andres
authors.initials: A
authors.lastname: Hernandez
authors.affiliation: Department of Physiology and Pharmacology.
authors.forename: Niklas
authors.initials: N
authors.lastname: Ivarsson
authors.affiliation: Department of Physiology and Pharmacology.
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Cheng
authors.affiliation: Department of Laboratory Medicine.
authors.forename: Karin
authors.initials: K
authors.lastname: Naess
authors.affiliation: Center for Inherited Metabolic Disease (CMMS), Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Rolf
authors.initials: R
authors.lastname: Wibom
authors.affiliation: Center for Inherited Metabolic Disease (CMMS), Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Nicole
authors.initials: N
authors.lastname: Lesko
authors.affiliation: Center for Inherited Metabolic Disease (CMMS), Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Helene
authors.initials: H
authors.lastname: Bruhn
authors.affiliation: 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.
authors.forename: Anna
authors.initials: A
authors.lastname: Wedell
authors.affiliation: Department of Laboratory Medicine, Center for Inherited Metabolic Disease (CMMS), Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Christoph
authors.initials: C
authors.lastname: Freyer
authors.affiliation: Department of Physiology and Pharmacology.
authors.forename: Shi-Jin
authors.initials: SJ
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Pharmacology.
authors.forename: Mattias
authors.initials: M
authors.lastname: Carlström
authors.affiliation: Department of Physiology and Pharmacology.
authors.forename: Johanna T
authors.initials: JT
authors.lastname: Lanner
authors.affiliation: Department of Physiology and Pharmacology.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Andersson
authors.affiliation: Department of Physiology and Pharmacology.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Bruton
authors.affiliation: Department of Laboratory Medicine, Center for Inherited Metabolic Disease (CMMS), Karolinska University Hospital, Stockholm, Sweden anna.wredenberg@ki.se hakan.westerblad@ki.se.
authors.forename: Anna
authors.initials: A
authors.lastname: Wredenberg
authors.affiliation: Department of Physiology and Pharmacology, anna.wredenberg@ki.se hakan.westerblad@ki.se.
authors.forename: Håkan
authors.initials: H
authors.lastname: Westerblad
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000235:genetics; D016572:Cyclosporine / Q000627:therapeutic use*; D004272:DNA, Mitochondrial; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D017240:Mitochondrial Myopathies / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation
chemical_list: D000081406:Peptidyl-Prolyl Isomerase F; D004272:DNA, Mitochondrial; C000631446:PPIF protein, mouse; D016572:Cyclosporine; D021983:Cyclophilins; D002118:Calcium