title: Increased mitochondrial mass in mitochondrial myopathy mice.
abstract: 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.
authors.affiliation: Department of Medical Nutrition and Biosciences, Karolinska Institute, Huddinge Hospital, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Wredenberg
authors.forename: Rolf
authors.initials: R
authors.lastname: Wibom
authors.forename: Hans
authors.initials: H
authors.lastname: Wilhelmsson
authors.forename: Caroline
authors.initials: C
authors.lastname: Graff
authors.forename: Heidi H
authors.initials: HH
authors.lastname: Wiener
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Burden
authors.forename: Anders
authors.initials: A
authors.lastname: Oldfors
authors.forename: Håkan
authors.initials: H
authors.lastname: Westerblad
authors.forename: Nils-Göran
authors.initials: NG
authors.lastname: Larsson
mesh_terms: 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
chemical_list: D004272:DNA, Mitochondrial; D004275:DNA, Ribosomal; D012337:RNA, Ribosomal, 18S