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Mitochondrial myopathies

H. Westerblad, Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden. (Introduced by D.G Allen)

Mitochondrial myopathies are caused by genetic mutations that directly influence mitochondrial function. We have studied mechanisms underlying the impaired muscle function in several mouse models of mitochondrial myopathy. Experiments were mainly performed on single muscle fibres where force and [Ca2+]i were simultaneously measured. Furthermore, mitochondrial matrix [Ca2+] ([Ca2+]mit) and reactive oxygen species (ROS) were measured as these parameters have been implicated in the development of mitochondrial disorders. Protein changes that might cause the observed functional changes were assessed. Experiments were performed on muscles that were isolated after the mouse had been killed by rapid neck disarticulation. The results show that muscle weakness due to a decreased sarcoplasmic reticulum (SR) Ca2+ release is a key defect in mitochondrial myopathies (Aydin et al., 2009). The decreased Ca2+ release can be explained by a reduced SR Ca2+ loading capacity. Increased [Ca2+]mit during repeated contractions appears to be an important cause of the muscle weakness, and muscle function is improved when the mitochondrial Ca2+ uptake is inhibited. We saw no signs of increased ROS production in mitochondrial myopathy muscles.

In conclusion, the observed changes in Ca2+ handling can be seen as adaptive responses to progressively failing mitochondrial ATP production. A reduced SR Ca2+ release will effectively decrease ATP expenditure, and increased [Ca2+]mit can stimulate mitochondrial respiration. However, reduced SR [Ca2+] causes muscle weakness and increased [Ca2+]mit may be harmful in the long run by inducing cell damage.

Aydin J, Andersson DC, Hänninen SL, Wredenberg A, Tavi P, Park CB, Larsson NG, Bruton JD & Westerblad H. (2009). Increased mitochondrial Ca2+ and decreased sarcoplasmic reticulum Ca2+ in mitochondrial myopathy. Human Molecular Genetics 18, 278-288.