Mitochondrial myopathy and

The condition known as fatal infantile mitochondrial myopathy and renal dysfunction involves severe diminution or absence of most oxidoreductases of the respiratory chain. MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke) is an inherited condition due to NADHiubiquinone oxidoreductase (complex I) or cytochrome oxidase deficiency. It is caused by a muta-... 

Although DNA mutations in nuclear DNA may cause mitochondrial dysfunction, the majority of genetically defined mitochondrial diseases are caused by mutations in mtDNA (M15, PI, S4). Point mutations and deletions of mtDNA have been reported to be associated with or responsible for mitochondrial myopathies and/or encephalomyopathies (M15, PI, S4). Patients with such diseases usually manifest major clinical symptoms early in life and at a later stage may develop additional multisystem disorders such as encephalopathy and/or peripheral neuropathy. Most of the mitochondrial myopathies occur sporadically and are often caused by large-scale mtDNA deletions (PI). However, there are several reports on maternally inherited mitochondrial myopathy and familial mitochondrial myopathy. These patients usually harbor a specific mtDNA mutation and often exhibit defects in NADH-CoQ reductase and/or cytochrome c oxidase. 

In 1997, Graham et al. (G6) reported that mice lacking the nuclear gene encoding the heart/muscle isoform of ANTI exhibit a severe defect in mitochondrial respiration, a dramatic proliferation of mitochondria in skeletal muscle, and cardiac hypertrophy. The mutant mice developed mitochondrial myopathy and cardiomyopathy associated with ragged-red muscle fibers, lactic acidosis, and severe exercise intolerance, which are similar to observations in patients with mtDNA diseases (G6, Wl). 

C2. Chan, A., Reichmann, H., Kogel, A., Beck, A., and Gold, R., Metabolic changes in patients with mitochondrial myopathies and effects of coenzyme Q10 therapy. J. Neurol. 245,681-685 (1998). 

K4. Kitaoka, H., Kameoka, K., Suzuki, Y., Sasaki, E., Majima, M., Takada, K., Katagiri, H., Oka, Y., and Ohsawa, N., A patient with diabetes mellitus, mitochondrial myopathy, and a mitochondrial gene mutation Confirmation of a gene mutation in cardiac muscle. Diabet. Res. Clin. Pract. 28, 207-212(1995). 

Ml 8. Miiller-Hocker, J., Ibel, H., Paetzke, I., Deufel, T., Endres, W., Kadenbach, B., Gokel, J. M., and Hubner, G., Fatal infantile mitochondrial myopathy and myopathy with heterogeneous tissue expression of combined respiratory chain deficiencies. Virchows Arch. A Pathol. Anat. Histopathol. 419, 55-362 (1991). 

Several inherited disorders are associated with faulty operation of the electron transport pathway. ATP production is diminished in such cases. These disorders are known as mitochondrial myopathies, and they are associated with the absence of specific polypeptide chains found in complexes I, III, or IV. In many cases, the problem may be traced to specific lesions in mitochondrial DNA, which codes for at least 13 polypeptide chains found in these complexes. Myopathies are tissue specific some affect the heart, others the skeletal muscle. Many are accompanied by lactic acidosis, because the inability to reduce NADH normally results in its accumulation and the channeling of pyruvate toward lactic acid production. In complex I disorders, the oxidation of FADH2 is not impeded. In complex III lesions, neither NADH nor FADH2 can be oxidized. However, use has been made by B. Chance and colleagues of menadione (Chapter 6) and ascorbic acid in such cases. The former can oxidize UQH2, whereas ascorbate can oxidize menadione and reduce cytochrome c. Marked clinical improvement in affected patients follows such treatment. 

Capaldi RA. Mitochondrial myopathies and respiratory chain proteins. Trends Biochem Sci April 144-148, 1988. 

Human DCA was used as a potential orally effective hypoglycemic agent. Only a slight sedation was noted in some patients. More recently, DCA has been evaluated with success in the treatment of lactic acidosis associated with severe malarial mitochondrial myopathy and liver transplantation. Although DCA is used in a variety of medical conditions, it presents little acute risk probably due to the smaller doses. 

Large mtDNA deletions account for most cases of ocular myopathy and Pearson s marrow/pancreas syndrome. Ocular myopathy patients can exhibit a variety of clinical symptoms, from mild chronic progressive external ophthalmoplegia (CPEO) to Kearns-Sayre Syndrome (KSS). These diseases are characterized by an early onset of ophthalmoplegia, atypical retinitis pigmentosa, mitochondrial myopathy, and usually cerebellar syndrome and cardiac conduction abnormalities. More than 120 different mtDNA deletions have been identified from patients tissues. Partial duplications of mtDNA have been detected in ocular myopathy and Pearson s syndrome, however, duplications are much rarer than spontaneous deletions in patients with these conditions. Exactly how partial mtDNA duplications arise is unknown. 

Kearns-Sayre syndrome Onset before 20 years of age, characterized by opthalmoplegia, atypical retinitis pigmentosa, mitochondrial myopathy, and one of the following cardiac conduction defect, cerebellar syndrome, or elevated CSF proteins. Deletion of contiguous segments of tRNA and OXPHOS polypeptides, or duplication mutations consisting of tandemly arranged normal mtDNA and an mtDNA with a deletion mutation. 

There is little qnestion from the ample literature reviewed above that age-related muscle atrophy and weakness is a mitochondrial "disease, jnst as predicted by Anita Harding in 1992. There isn t mnch we can do for mitochondrial myopathies and there isn t much we can do for sarcopenia. However, two sensible approaches to maintain our muscle fitness include diet and exercise. 

Shapira, Y., Cederbaum, S.D., Concilia, P.A., Nielsen, D. and Lippe, B.M. (1975), Familial poliodystrophy, mitochondrial myopathy and lactate acidemia. Neurology, 25,614. 

This complex consists of at least 25 separate polypeptides, seven of which are encoded by mtDNA. Its catalytic action is to transfer electrons from NADH to ubiquinone, thus replenishing NAD concentrations. Complex I deficiency has been described in myopathic syndromes, characterized by exercise intolerance and lactic acidemia. In at least some patients it has been demonstrated that the defect is tissue specific and a defect in nuclear DNA is assumed. Muscle biopsy findings in these patients are typical of those in many respiratory chain abnormalities. Instead of the even distribution of mitochondria seen in normal muscle fibers, mitochondria are seen in dense clusters, especially at the fiber periphery, giving rise to the ragged-red fiber (Figure 10). This appearance is a hallmark of many mitochondrial myopathies. 

In vivo, patients treated with AZT develop a mitochondrial myopathy with mitochondrial DNA depletion, deficiency of cytochrome c oxidase (complex IV), intracellular fat accumulation, high lactate production and marked phosphocreatine depletion (Lewis and Dalakas 1995 Dalakas 2001). Clinically, the patient presents with fatigue, myalgia, muscle weakness, wasting and elevated serum creatine kinase. Muscle biopsy shows ragged red fibers , the characteristic histopathologic changes of mitochondrial myopathy, cansed by subsarcolemmal accumulation of mitochondria (Lewis and Dalakas 1995). 

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke like episodes (MELAS) Mitochondrial tRNA (leu)... 

Phosphorus-31 MRS has been used widely to investigate mitochondria diseases in muscle. Trenell et al. measured an elevated ADP concentration and pHi in a group of mitochondrial myopathy (MM) patients, which is evidence of impaired oxidative ATP production in their skeletal mus-cle This study also showed that increased inspired oxygen concentration improves oxidative fimction in MM patients. In a separate study, Jeppesen et al. could not differentiate healthy subjects and MM patients using P MRS. ° They concluded the P MRS should not be a routine test in the diagnosis for MM patients. 

Mitochondrial Myopathy. A general deticiency of iron may ho implicated in mitochondrial myopathy, which is a complex disorder that affects muscular activity. It lias been suspected for a number of years that the disorder is caused hy a delect of mitochondrial-protein transport. H.H.V. Sdiarpa and a team of researchers (Royal Free Hospital. London) postulate that a deficiency of an iron-sulfur protein in muscle dehydrogenase may be the specific cause. 

Diaz, F., Thomas, C. K., Garcia, S., Hernandez, D. and Moraes, C. T. (2005) Mice lacking COXIO in skeletal muscle recapitulate the phenotype of progressive mitochondrial myopathies associated with cytochrome c oxidase deficiency. Hum Mol Genet 14, 2737-2748. 

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