ausblenden:
Schlagwörter:
Animals
Biological Transport
Calcium/*metabolism
Calcium-Binding Proteins/genetics/metabolism
DNA-Binding Proteins/genetics/metabolism
High Mobility Group Proteins/genetics/metabolism
Humans
Membrane Potential, Mitochondrial
Mice
Mice, Knockout
Mitochondria/genetics/*metabolism
Mitochondrial Myopathies/genetics/*metabolism
Muscle, Skeletal/metabolism
Oxidative Stress
Sarcoplasmic Reticulum/genetics/*metabolism
Zusammenfassung:
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 Ca(2+) handling is part of the mechanism of muscle dysfunction in mitochondrial myopathy. Force measurements were combined with measurements of cytosolic Ca(2+), mitochondrial Ca(2+) and membrane potential and reactive oxygen species in intact, adult muscle fibres. The results show reduced sarcoplasmic reticulum (SR) Ca(2+) storage capacity in Tfam KO muscles due to a decreased expression of calsequestrin-1. This resulted in decreased SR Ca(2+) 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 [Ca(2+)] during repeated contractions. Mitochondrial [Ca(2+)] 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 Ca(2+) handling are adaptive responses with long-term detrimental effects. Reduced SR Ca(2+) release likely decreases ATP expenditure, but it also induces muscle weakness. Increased [Ca(2+)](mit) will stimulate mitochondrial metabolism acutely but may also trigger cell damage.
