Human Molecular Genetics Advance Access originally published online on October 22, 2008
Human Molecular Genetics 2009 18(2):278-288; doi:10.1093/hmg/ddn355
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Increased mitochondrial Ca2+ and decreased sarcoplasmic reticulum Ca2+ in mitochondrial myopathy
1 Department of Physiology and Pharmacology 2 Department of Laboratory Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden 3 Department of Physiology and Biocenter Oulu, University of Oulu, Oulu, Finland
* To whom correspondence should be addressed. Tel +46 852487253; Fax: +46 8327026; Email: hakan.westerblad{at}ki.se
Received July 2, 2008; Revised August 21, 2008; Accepted October 20, 2008
Genetic mutations that affect mitochondrial function often cause skeletal muscle dysfunction. Here, we used mice with skeletal-muscle-specific disruption of the nuclear gene for mitochondrial transcription factor A (Tfam) to study whether changes in cellular Ca2+ handling is part of the mechanism of muscle dysfunction in mitochondrial myopathy. Force measurements were combined with measurements of cytosolic Ca2+, mitochondrial Ca2+ and membrane potential and reactive oxygen species in intact, adult muscle fibres. The results show reduced sarcoplasmic reticulum (SR) Ca2+ storage capacity in Tfam KO muscles due to a decreased expression of calsequestrin-1. This resulted in decreased SR Ca2+ release during contraction and hence lower force production in Tfam KO than in control muscles. Additionally, there were no signs of oxidative stress in Tfam KO cells, whereas they displayed increased mitochondrial [Ca2+] during repeated contractions. Mitochondrial [Ca2+] remained elevated long after the end of stimulation in muscle cells from terminally ill Tfam KO mice, and the increase was smaller in the presence of the cyclophilin D-binding inhibitor cyclosporin A. The mitochondrial membrane potential in Tfam KO cells did not decrease during repeated contractions. In conclusion, we suggest that the observed changes in Ca2+ handling are adaptive responses with long-term detrimental effects. Reduced SR Ca2+ release likely decreases ATP expenditure, but it also induces muscle weakness. Increased [Ca2+]mit will stimulate mitochondrial metabolism acutely but may also trigger cell damage.
Present address: Max Planck Institute for Biology of Ageing, Gleueler Str. 50a, Cologne, Germany.