Increased mitochondrial mass in mitochondrial myopathy mice.
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.
Wredenberg
Anna
A
Department of Medical Nutrition and Biosciences, Karolinska Institute, Huddinge Hospital, Sweden.
Wibom
Rolf
R
Wilhelmsson
Hans
H
Graff
Caroline
C
Wiener
Heidi H
HH
Burden
Steven J
SJ
Oldfors
Anders
A
Westerblad
Håkan
H
Larsson
Nils-Göran
NG
D000818:Animals; D003433:Crosses, Genetic; D004272:DNA, Mitochondrial / Q000235:genetics*; D004275:DNA, Ribosomal / Q000235:genetics; D004195:Disease Models, Animal; D004558:Electric Stimulation; D006579:Heterozygote; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008931:Mitochondria, Muscle / Q000473:pathology* / Q000502:physiology; D017240:Mitochondrial Myopathies / Q000235:genetics*; D009119:Muscle Contraction / Q000502:physiology; D018656:Muscle Fibers, Fast-Twitch / Q000473:pathology; D009126:Muscle Relaxation; D010101:Oxygen Consumption / Q000235:genetics; D012337:RNA, Ribosomal, 18S / Q000235:genetics; D012016:Reference Values; D013997:Time Factors
D004272:DNA, Mitochondrial; D004275:DNA, Ribosomal; D012337:RNA, Ribosomal, 18S