Therapeutic Trials in Muscular Dystrophy

Enomoto, Akira; Bradley, Walter G.

doi:10.1001/archneur.1977.00500240059010

Arch Neurol

1977

DOI: 10.1001/archneur.1977.00500240059010

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Therapeutic Trials in Muscular Dystrophy

Akira Enomoto

Walter G. Bradley

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1979

1983

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Cited by 21 publications

(3 citation statements)

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“…In succinate dehydrogenase preparations some fibers' that appeared normal in hematoxylin and eosin stains showed patchy or lost mitochondrial staining. Fifteen of the 16 treated animals had no significant histological changes in their muscle, whereas 19 of the 24 untreated animals' muscle sections showed a necrotizing myopathy (P < 0;001;' Table 1).…”

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Successful treatment of murine muscular dystrophy with the proteinase inhibitor leupeptin.

Sher¹,

Stracher²,

Shafiq³

et al. 1981

Proc. Natl. Acad. Sci. U.S.A.

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Mice with genetic muscular dystrophy were treated with intraperitoneal injections of the proteinase inhibitor leupeptin, beginning before the onset of weakness. A significant number of the treated animals failed to develop histological evidence ofdystrophy, compared with controls. Leupeptin treatment prevented (or delayed) the onset of muscular dystrophy in this experiment. In muscular dystrophy, there is biochemical and morphological evidence of abnormality of the muscle cell plasma membrane (1-3). Such defective membranes may allow calcium influx, leading to activation of proteinases and initiating muscle fiber necrosis (4-6). The. eventual severe loss of sarcoplasmic and contractile proteins in dystrophy is associated with increased activity of acidic and neutral proteinases (7-10).The proteinase inhibitor leupeptin (11) is known to inhibit cathepsin B and calcium-activated neutral endopeptidase, proteinases thought to play an important role in muscle catabolism in dystrophy. Leupeptin and pepstatin (a similar proteinase inhibitor that acts on cathepsin D) (11, 12), delay degeneration ofdystrophic chicken muscle in vitro and in vivo (13-15). Likewise, normal and dystrophic mouse muscles show decreased protein degradation in vitro when incubated with leupeptin (16).These findings suggest that leupeptin may be able to limit proteolysis in early dystrophic lesions, minimizing muscle fiber damage. Therefore, we studied the effects of leupeptin treatment of genetically dystrophic mice.We used C57BL/6J dy2J/dy2J mice (17, 18), the progeny of matings between dystrophic homozygous dy2J males and brown females with transplanted ovaries from homozygous dyJ females, or of matings between the homozygous littermates that resulted from the first breeding pairs. Sixteen

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“…A previous study of combined leupeptin and pepstatin treatment ofdystrophic mice showed no effect (19). The were homozygous dy mice and treatment via the subcutaneous route was begun at 35 days, at a time when the disease is well advanced in this strain.…”

mentioning

confidence: 99%

Successful treatment of murine muscular dystrophy with the proteinase inhibitor leupeptin.

Sher¹,

Stracher²,

Shafiq³

et al. 1981

Proc. Natl. Acad. Sci. U.S.A.

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“…In 1976 reported that degenerative changes in dystrophic chick (Connecticut strain) muscle cultures could be prevented by antiproteinases such as leupeptin and pepstatin, and these inhibitors have also been shown to inhibit protein degradation in other systems (Iodice, 1976;Libby & Goldberg, 1978). It has since been claimed that the treatment of dystrophic chickens (Connecticut strain) (Stracher et al, 1978) and mice (129/ReJ-dy/dy) (Schorr et al, 1978) led to a significant improvement, although Enomoto & Bradley (1977) found that antipain, pepstatin and leupeptin had no effect on the lifespan or activity of 129/ReJ-dy/dy mice.…”

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Protein degradation in skin fibroblasts from patients with Duchenne muscular dystrophy

Statham¹,

Witkowski²,

Dubowitz³

1980

Biochemical Journal

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The rates of degradation of [3H]leucine-labelled proteins have been measured in cultures of skin fibroblasts obtained from normal controls (five subjects) and patients with Duchenne muscular dystrophy (six subjects). Cultures were incubated with [3H]leucine (10 microCi/ml) for 60 min to label "short-lived" proteins, and with [3H]leucine (5 microCi/ml) for 60 h to label "long-lived" proteins. Optimal wash procedures were devised for removal of [3H]leucine from the extracellular space and from cell pools before beginning degradation measurements. Re-utilization of [3H]leucine released from degraded labelled proteins was prevented by supplementing the medium with 4mM-leucine. Rates of degradation did not depend on the growth state of the cells or on cell age over the range used (passages eight-20). Degradation of long-lived proteins was approximately linear over a 24h period, at a rate of 1.0% per h. 30% of short-lived protein was degraded within 6h. No differences were observed between protein degradation in normal fibroblasts and in those from patients with Duchenne muscular dystrophy.

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Muscle wasting in muscular dystrophy: Decreased protein synthesis or increased degradation?

Griggs

Reinnie

1983

Annals of Neurology

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The cause of the muscular dystrophies remains unknown. Recent publications summarize current thoughts on pathogenesis 162, 631. Because of their relatively high incidence and severity, Duchenne dystrophy and myotonic dystrophy have received the greatest attention. Although the primary defect:; in these disorders are obscure, a feature common to all muscular dystrophies is loss of skeletal muscle, which must arise because of an imbalance between muscle protein synthesis and degradation. The mechanisms of muscle protein turnover are currently under intensive study, and approaches have recently been developed for their investigation in patients with neuromuscular disease /23, 601. Further, since agents are now available that may alter protein synthesis or degradarion {ll, 37,47, 48,65, 681, there is some hope of modifying the course of human neuromuscular disease. 'The importance of correctly describing and understanding the processes involved in cell necrosis and regeneration is highlighted by a paper in this issue of Annalr of Neurology 1741.The relevance of much of the following discussion depends upon the reliability of the methods used to measure the components of protein turnover. We will not, however, further discuss the technical problems involved except to say that we believe protein synthlesis in muscle is best measured in vivo or in perfused !jystems by methods that utilize constant infusion /45] or large flooding doses of tracer agents [18], and that tissue culture and isolated muscle systems may give unreliable results. Regrettably, there are no good direct methods of measuring muscle protein degradation, especially in living human beings. Nevertheless, in a discussion of the effects of disease on protein turnover, measurements made in vivo in humans and animals carry the most conviction. (For a discussion of the pros and cons of various methods, see 128, 731.)The factors controlling muscle protein turnover theoretically may produce their effects by altering either synthesis or degradation of protein. In skeletal muscle, however, protein synthesis is clearly the modulated process that is of primary regulatory importance during both the rapid increases that occur with feeding C34, 591 and with induced muscle hypertrophy 121, 28, 341and also during starvation, diabetes, and chronic corticosteroid treatment 145, 46, 551. The situation as regards muscle protein degradation is less clear because of the methodological difficulties in estimating degradation, but evidence is accumulating 1461 that in most circumstances which entail alteration of muscle mass, protein degradation simply adapts to changes in synthesis in a way that effectively limits the extent of the change, i.e., so-called anabolic and catabolic degradation 1431. Muscle Protein Synthesis in Human BeingsThe use of stable isotopes has allowed measurement of muscle protein synthesis in humans. This work was pioneered by Halliday and McKeran 1261, who used "N-labeled lysine delivered by constant infusion over periods lasting up to 12 hours and measu...

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Therapeutic Trials in Muscular Dystrophy

Cited by 21 publications

References 28 publications

Successful treatment of murine muscular dystrophy with the proteinase inhibitor leupeptin.

Successful treatment of murine muscular dystrophy with the proteinase inhibitor leupeptin.

Protein degradation in skin fibroblasts from patients with Duchenne muscular dystrophy

Muscle wasting in muscular dystrophy: Decreased protein synthesis or increased degradation?

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