title: Muscle denervation promotes opening of the permeability transition pore and increases the expression of cyclophilin D.
abstract: Loss of neural input to skeletal muscle fibres induces atrophy and degeneration with evidence of mitochondria-mediated cell death. However, the effect of denervation on the permeability transition pore (PTP), a mitochondrial protein complex implicated in cell death, is uncertain. In the present study, the impact of 21 days of denervation on the sensitivity of the PTP to Ca2+-induced opening was studied in isolated muscle mitochondria. Muscle denervation increased the sensitivity to Ca2+-induced opening of the PTP, as indicated by a significant decrease in calcium retention capacity (CRC: 111 +/- 12 versus 475 +/- 33 nmol (mg protein)(-1) for denervated and sham, respectively). This phenomenon was partly attributable to in vivo mitochondrial and whole muscle Ca2+ overload. Cyclosporin A, which inhibits PTP opening by binding to cyclophilin D (CypD), was significantly more potent in mitochondria from denervated muscle and restored CRC to the level observed in mitochondria from sham-operated muscles. In contrast, the CypD independent inhibitor trifluoperazine was equally effective at inhibiting PTP opening in sham and denervated animals and did not correct the difference in CRC between groups. This phenomenon was associated with a significant increase in the content of the PTP regulating protein CypD relative to several mitochondrial marker proteins. Together, these results indicate that Ca2+ overload in vivo and an altered expression of CypD could predispose mitochondria to permeability transition in denervated muscles.
authors: Département de kinésiologie, Université de Montréal, P.O. Box 6128 Centre-Ville, Montreal, Quebec, Canada, H3C 3J7.
authors: Kristina
authors: K
authors: Csukly
authors: Alexis
authors: A
authors: Ascah
authors: Jimmy
authors: J
authors: Matas
authors: Phillip F
authors: PF
authors: Gardiner
authors: Eric
authors: E
authors: Fontaine
authors: Yan
authors: Y
authors: Burelle