Increased mitochondrial mass in mitochondrial myopathy mice

Autor: Anna Wredenberg, Håkan Westerblad, Steven J. Burden, Anders Oldfors, Caroline Graff, Nils-Göran Larsson, Heidi H. Wiener, Rolf Wibom, Hans Wilhelmsson
Rok vydání: 2002
Předmět:
Zdroj: Proceedings of the National Academy of Sciences. 99:15066-15071
ISSN: 1091-6490
0027-8424
DOI: 10.1073/pnas.232591499
Popis: We have generated an animal model for mitochondrial myopathy by disrupting the gene for mitochondrial transcription factor A ( Tfam ) in skeletal muscle of the mouse. The knockout animals developed a myopathy with ragged-red muscle fibers, accumulation of abnormally appearing mitochondria, and progressively deteriorating respiratory chain function in skeletal muscle. Enzyme histochemistry, electron micrographs, and citrate synthase activity revealed a substantial increase in mitochondrial mass in skeletal muscle of the myopathy mice. Biochemical assays demonstrated that the increased mitochondrial mass partly compensated for the reduced function of the respiratory chain by maintaining overall ATP production in skeletal muscle. The increased mitochondrial mass thus was induced by the respiratory chain deficiency and may be beneficial by improving the energy homeostasis in the affected tissue. Surprisingly, in vitro experiments to assess muscle function demonstrated that fatigue development did not occur more rapidly in myopathy mice, suggesting that overall ATP production is sufficient. However, there were lower absolute muscle forces in the myopathy mice, especially at low stimulation frequencies. This reduction in muscle force is likely caused by deficient formation of force-generating actin–myosin cross bridges and/or disregulation of Ca 2+ homeostasis. Thus, both biochemical measurements of ATP-production rate and in vitro physiological studies suggest that reduced mitochondrial ATP production might not be as critical for the pathophysiology of mitochondrial myopathy as thought previously.
Databáze: OpenAIRE