Muscular dystrophies muscle enzymes

In 1956 selenium was identified (123) as an essential micronutrient iu nutrition. In conjunction with vitamin E, selenium is effective iu the prevention of muscular dystrophy iu animals. Sodium selenite is adrninistered to prevent exudative diathesis iu chicks, a condition iu which fluid leaks out of the tissues white muscle disease iu sheep and infertility iu ewes (see Eeed ADDITIVES). Selenium lessens the iacidence of pneumonia iu lambs and of premature, weak, and stillborn calves controls hepatosis dietetica iu pigs and decreases muscular inflammation iu horses. White muscle disease, widespread iu sheep and cattle of the selenium-deficient areas of New Zealand and the United States, is insignificant iu high selenium soil areas. The supplementation of animal feeds with selenium was approved by the U.S. EDA iu 1974 (see Eeed additives). Much of selenium s metaboHc activity results from its involvement iu the selenoproteia enzyme, glutathione peroxidase. 

As with many enzymes the role of AMP aminohydrolase in the hierarchy of metabolic catalysts is not clearly understood. Enzymic activity in muscle is markedly reduced in the dystrophic mouse (161, 162), in humans suffering from Duchanne type muscular dystrophy (163), in hypokaliemic periodic paralysis (164), and upon denervation of normal and dystrophic mouse gastronemii (165). Activity is reported to increase in both transplanted and primary hepatomas (151) and in precancerous livers prior to the onset of neoplasia induced by feeding or by intraabdominal injections of the potent carcinogen 3 -methyl-4-dimethyl-aminoazobenzene (166). The weak carcinogen, 4 -methyl-4-dimethyl-aminoazobenzene was not effective (166). Increases in enzyme activity concomitant with altered nuclear-nucleolar morphology, nuclear RNA content, and nuclear RNA biosynthesis were also observed after injections of thioacetamide, a hepatocarcinogen (167, 168). 

In contrast to arsenic, trace concentrations of selenium are essential for human and animal health. Until the late 1980s, the only known metabolic role for selenium in mammals was as a component of the enzyme glutathione peroxidase (GSH-Px), an anti-oxidant that prevents cell degeneration. There is now growing evidence, however, that a seleno-enzyme is involved in the synthesis of thyroid hormones (Arthur and Beckett, 1989 G. F. Combs and S. B. Combs, 1986). Selenium dehciency has been linked to cancer, AIDS, heart disease, muscular dystrophy, multiple sclerosis, osteoarthropathy, immune system and reproductive disorders in humans, and white muscle disease in animals (Levander,... 

In muscular dystrophy, therefore, the maintenance of considerable serum activities of soluble enzymes almost certainly of sarcoplasmic origin, and known to be subject to very rapid and continuous clearance from serum, strongly argues their ceaseless copious discharge from dystrophic muscle. The likelihood at once arises that the dystrophic muscle cell membrane is unduly permeable to these enzymes, that their activities are diminished within the cell, and that because of such lavish discharge even reduced intracellular activities could be preserved only by unusually rapid renewal. These probabilities receive substantial support from the results obtained by other workers. 

Because of the rapid increase of connective tissue in muscular dystrophy, ultimately far exceeding in quantity any muscle tissue left, determinations of enzyme content of dystrophic muscle are invariably made... 

The copious muscle enzyme efflux in Duchenne-type muscular dystrophy, giving gross serum elevations despite the rapid serum clearance, may well deplete some muscle enzymes that so much aldolase still remains may indicate a replacement so rapid that, if applied to the transaminases and to lactic dehydrogenase, the muscle content may be maintained or even increased, since their serum elevations, though considerable, are proportionately much less than that of aldolase. 

Again, continued loss of dystrophic muscle must diminish its total enzyme efflux. In Duchenne-type muscular dystrophy the highest serum enzyme elevations occur in early childhood, diminish as the disease pro-... 

Thus in muscular dystrophy it is apparent that both the mean elevations of the serum enzyme values and the magnitudes of their variations upon physical activity are proportional to the mass of dystrophic muscle remaining and to the severity of the disease in it. Both are thus greater in early than in evident Duchenne-type dystrophy, less in limb-girdle dystrophy, and least in myotonia congenita. Further, though serum creatine kinase has been found to be an exceedingly delicate index of myopathy (A2, S14), for present purposes serum aldolase is suflBciently... 

Blood enzyme tests can detect the abnormalities associated with progressive muscular dystrophy early on, even before symptoms are clearly evident. Muscle tissue is rich in creatine and, when muscles are diseased, the creatine leaks into the blood and can be measured as creatine kinase (CK). The normal level of CK is about 160 lU/L, but an individual with Duchene muscular dystrophy may have CK levels as high as 15,000-35,000 lU/L. If the diagnosis is in doubt, genetic studies and muscle biopsy can also be done. The recent isolation of the Duchenne gene and the discovery that dystrophin is the abnormal encoded protein makes a precise molecular diagnosis possible. It also offers hope that the genetic basis for other dystrophies will be discovered soon. 

Serum CK activity is greatly elevated in all types of muscular dystrophy. In progressive muscular dystrophy (particularly Duchenne sex-linked muscular dystrophy), enzyme activity in serum is highest in infancy and childhood (7 to 10 years of age) and may be increased long before the disease is clinically apparent. Serum CK activity characteristically falls as patients get older and as the mass of functioning muscle diminishes with the progression of the disease. About 50% to 80% of the asymptomatic female carriers of Duchenne dystrophy show threefold to sixfold increases of CK activity, but values may be normal if specimens are obtained after patients have experienced a period of physical inactivity. Quite high values of CK are noted in... 

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... 

Adenylate kinase, which is abundant in muscle as in many other tissues, decreases in dystrophic mouse and human muscle (H6, P7). This enzyme, by interconverting adenine nucleotides, probably functions in the control of glycolysis it seems reasonable to suppose, therefore, that its activity may be governed by the same factors which influence glycolytic enzymes, as discussed above. A severe decline in the activity of AMP deaminase occurs in muscular dystrophy (P6, P7) and also in denervated muscle (M12) and in some cases of muscle affected by hypokalemic periodic paralysis (E6). Skeletal muscle normally contains a higher concentration of this enzyme than other tissues in fact, it is almost absent from some, such as liver. Its physiological function, and hence the significance of the sharp decline in its activity in diseased muscle, is still a matter of speculation. 

Early histochemical studies (G2) indicated an increase in human dystrophic muscle of a number of enzymes responsible for dephosphoryl-ating certain nucleotides. These enzymes appeared to be largely located in the proliferated connective tissue, and the authors suggested that muscular dystrophy may be basically a connective tissue disease. There is little or no evidence, however, to substantiate this speculation. Quantitative studies (P6, R3) have confirmed an increase in the dephosphorylation of AMP by diseased muscle, but it is not clear to what extent, in muscle, this activity is due to a specific enzyme. An increase in the rate of hydrolysis of NAD in denervated muscle has been reported (T4). 

It is also not entirely clear why the blood levels of individual enzymes in muscular dystrophy differ so widely. In some instances, even, there appears to be no increase. Thus blood AMP deaminase levels are barely raised (P8), and Rowland and co-workers (RIO) were unable to detect phosphofructokinase or myoglobin by enzymological or immunochemical techniques. The relative abundance of the enzyme in muscle is obviously important indeed, Dawson (D2) found that in vitro there was a good correlation between the amounts in muscle and the amounts leaking out. In Duchenne dystrophy, however, there is a poor parallel between the concentrations in muscle and blood (P8). The size and shape of an enzyme molecule would be expected to influence its rate of leakage, and a further factor is the attachment of an enzyme to intracellular structures there is some evidence that even the soluble enzymes of muscle may be, in some manner bound within the fibers (A2, H17). Probably other factors also are involved. 

Muscle cells which arc damaged will leak creatine kina.se into the plasma. This enzyme exists in different isoforms. CK-MM or total CK is used as an index of skeletal mu.scle damage. Very high serum levels may be expected in patients who have been convulsing or have muscular damage due to electrical shock or crush injury. Creatine kinase concentrations may also be high in acute spells in muscular dystrophy. For these rea.sons, when CK is used as an indicator of myocardial infarction. it is better to measure the MB... 

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