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

Abstract

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

Metagenomic analysis of nepoviruses: diversity, evolution and identification of a genome region in members of subgroup A that appears to be important for host range

“…Similarly, diversity studies and phylogenetic analysis have been reported for members of the family Secoviridae , including nepoviruses [ 45 , 51 ]. However, several new nepoviruses have been characterized recently, and the number of complete genome sequences of nepovirus isolates has increased exponentially in the past five years [ 1 , 2 , 4 , 12 , 15 , 18 , 23 – 25 , 41 , 50 , 55 , 56 , 58 ]. In this study, we built on these latest advancements in nepovirus research and carried out metagenomic analysis.…”

Purification and properties of different isoforms of bovine cathepsin B

“…Other important functions for this cysteine proteinase are its potential involvement in the processing of proinsulin (Docherty et al 1983) and other hormones, including endorphin (Suhar and Marks 1979) and proenkephalin (Marks et al 1986). Cathepsin B is also implicated in muscular dystrophy (Sher et al 1981;Stracher et al 1978).…”

Mechanism of Microbial Metabolite Leupeptin in the Treatment of COVID-19 by Traditional Chinese Medicine Herbs

“…1A ) is a secondary metabolite produced by actinomycetes ( 3 – 6 ), which has broad-spectrum protease-inhibitory activities, including serine, cysteine, and threonine proteases ( 7 – 11 ). Leupeptin treatment can prevent or delay muscular dystrophy in mouse or chicken models ( 12 ). Rabbits treated with leupeptin did not develop experimental autoimmune myasthenia gravis despite repeated acetylcholine receptor injections ( 13 ).…”