Muscle denervation promotes opening of the permeability transition pore and increases the expression of cyclophilin D
- 19 June 2006
- journal article
- Published by Wiley in The Journal of Physiology
- Vol. 574 (1), 319-327
- https://doi.org/10.1113/jphysiol.2006.109702
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.Keywords
This publication has 48 references indexed in Scilit:
- Exercise training induces respiratory substrate-specific decrease in Ca2+-induced permeability transition pore opening in heart mitochondriaAmerican Journal of Physiology-Heart and Circulatory Physiology, 2006
- Apoptotic responses to hindlimb suspension in gastrocnemius muscles from young adult and aged ratsAmerican Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2005
- Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemiaProceedings of the National Academy of Sciences, 2005
- Age-related differences in apoptosis with disuse atrophy in soleus muscleAmerican Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2005
- Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell deathNature, 2005
- Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell deathNature, 2005
- Regulated and unregulated mitochondrial permeability transition pores: a new paradigm of pore structure and function?FEBS Letters, 2002
- Role of Substrates in the Regulation of Mitochondrial Function In SituIUBMB Life, 2001
- Apoptosis, DNA damage and ubiquitin expression in normal and mdx muscle fibers after exerciseFEBS Letters, 1995
- The mitochondrial permeability transitionBiochimica et Biophysica Acta (BBA) - Reviews on Biomembranes, 1995