Myopathy oxide

Central core disease (CCD) is an autosomal dominant, non-progressive myopathy characterized by hypotonia and proximal muscle weakness in infancy. CCD is named after detection of characteristic central cores that lack both mitochondria and oxidative enzyme... 

This complex consists of four subunits, all of which are encoded on nuclear DNA, synthesized on cytosolic ribosomes, and transported into mitochondria. The succinate dehydrogenase (SDH) component of the complex oxidizes succinate to fumarate with transfer of electrons via its prosthetic group, FAD, to ubiquinone. It is unique in that it participates both in the respiratory chain and in the tricarboxylic acid (TC A) cycle. Defects of complex II are rare and only about 10 cases have been reported to date. Clinical syndromes include myopathy, but the major presenting features are often encephalopathy, with seizures and psychomotor retardation. Succinate oxidation is severely impaired (Figure 11). 

Clofibrate causes a necrotizing myopathy, particularly in patients with renal failure, nephrotic syndrome or hypothyroidism. The myopathy is painful and myokymia of unknown origin is sometimes present. The mechanism of damage is not known, but p-chlorophenol is a major metabolite of clofibrate and p-chlorophe-nol is a particularly potent uncoupler of cellular oxidative phosphorylation and disrupts the fluidity of lipid membranes. Muscle damage is repaired rapidly on the cessation of treatment. 

Corticosteroids a chronic painless myopathy associated with the long-term use of corticosteroids is a particularly common example of drug-induced muscle disorder. It is almost certain that mild cases are overlooked because steroids are so frequently used to treat inflammatory myopathies such as polymyositis. Fluorinated steroids are particularly frequently implicated, and the incidence of drug-induced muscle disease is dose and time-related. The presence of muscle weakness can even complicate topical steroid therapy. Corticosteroid-induced myopathy is mediated via intramuscular cytosolic steroid receptors. The steroid-receptor complexes inhibit protein synthesis and interfere with oxidative phosphorylation. The myopathy is associated with vacuolar changes in muscle, and the accumulation of cytoplasmic glycogen and mitochondrial aggregations. 

Mitochondrial diseases are often expressed as neuropathies and myopathies because brain and muscle are highly dependent on oxidative phosphorylation. Mitochondrial genes code for some of the components of the electron transport chain and oxidative phosphorylation, as well as some mitochondrial tRNA molecules. 

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. 

P7. Piccolo, G., Banfi, P., Azan, G., Rizzuto, R., Bisson, R., Sandona, D., and Bellomo, G., Biological markers of oxidative stress in mitochondrial myopathies with progressive external ophthalmoplegia. J. Neurol. Sci. 105, 57-60 (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. 

Primary carnitine deficiency is caused by a deficiency in the plasma-membrane carnitine transporter. Intracellular carnitine deficiency impairs the entry of long-chain fatty acids into the mitochondrial matrix. Consequently, long-chain fatty acids are not available for p oxidation and energy production, and the production of ketone bodies (which are used by the brain) is also impaired. Regulation of intramitochondrial free CoA is also affected, with accumulation of acyl-CoA esters in the mitochondria. This in turn affects the pathways of intermediary metabolism that require CoA, for example the TCA cycle, pyruvate oxidation, amino acid metabolism, and mitochondrial and peroxisomal -oxidation. Cardiac muscle is affected by progressive cardiomyopathy (the most common form of presentation), the CNS is affected by encephalopathy caused by hypoketotic hypoglycaemia, and skeletal muscle is affected by myopathy. 

Jeyarasasingam, G., Yeluashvili, M., Quik, M. (2000). Nitric oxide is involved in acetylcholinesterase inhibitor-induced myopathy in rats. J. Pharmacol. Exp. Ther. 295 314-20. 

Initially, most of the adverse effects seen with zidovudine use (in particular hematological effects) were attributed to interference with cellular DNA replication. However, DNA replication also occurs in mitochondria. Mitochondrial DNA encodes some of the enzymes used for oxidative phosphorylation. Only recently has it been hjrpothesized that inhibition of this pathway could lead to mitochondrial toxicity and be responsible for most of the toxicity seen with NRTIs, including polyneuropathy, myopathy, cardiomyopathy, steatosis, lactic acidosis, exocrine pancreas failure, bone marrow failure, and proximal tubular dysfunction (11). These adverse effects are also a compilation of the clinical features seen in several genetic mitochondrial cytopathies. 

The role of selenium in human medicine has been reviewed. Animal studies in the 1950s demonstrated the nutritionally beneficial, effects of selenium by showing that there was a selenium-responsive liver necrosis in vitamin E-deficient rats. There are important selenium-dependent diseases in farm animals, such as white muscle disease in sheep and cattle, and myopathy of cardiac and skeletal muscle in lambs and calves. In these animals, some cause of oxidative stress, such as increased physical activity or vitamin E deficiency—together witli dietary selenium deficiency—is required to elicit the disease. 

Beyond phase I (oxidative) and phase II (conjugative) statin metabolism, variability in membrane transport also contributes strongly to myopathy risk. The organic anion transporting... 

A slowly progressive congenital neuromuscular disorder was reported in which the respiratory chain-linked energy transfer at a level common to all three energy coupling sites of respiratory chain was defective.52 Uncouplers of mitochondrial oxidative phosphorylation (2,4-dinitrophenol and carbonylcyanide-m-chlorophenylhydrazone) (5) produced mitochondrial myopathy in rats.53... 

In contrast with the fall in the activity of muscle glycolytic enzymes in human muscular dystrophy, Dreyfus and his colleagues (DIO) found little or no decrease in the concentrations of certain enzymes involved in oxidative breakdown of fuel, notably succinate dehydrogenase, cytochrome oxidase, fumarase, and aconitase. In the mouse myopathy, the concentration of cytochrome oxidase is increased (W12) elevated levels of respiratory enzymes have been reported also in myopathy resulting from vitamin E deficiency (D6) and in genetically dystrophic chickens... 

An interesting hypermetabolic myopathy was discovered and biochemically explored by Luft et al. (L7). There was no evidence of hyperthyroidism, and mitochondria from biopsied muscle had a high rate of respiration and a loosely coupled state of oxidative phosphorylation. A few other cases of unusual myopathies with loosely coupled mitochondria have since been described (e.g., S12), although it does not seem that this is a single disease entity. 

J2. Jacobson, B. E., Blanchaer, M. C., and Wrogemann, K., Defective respiration and oxidative phosphorylation in muscle mitochondria of hamsters in the late stages of hereditary muscular dystrophy. Can. J. Biochem. 48, 1037-1042 (1970), J3. Jenkins, K. J., Ketone body metabolism in nutritional myopathy. Can. J. Biochem. 42, 1153-1160 (1964). 

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