Document Detail


Leupeptin-based inhibitors do not improve the mdx phenotype.
MedLine Citation:
PMID:  20844259     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Calpain activation has been implicated in the disease pathology of Duchenne muscular dystrophy. Inhibition of calpain has been proposed as a promising therapeutic target, which could lessen the protein degradation and prevent progressive fibrosis. At the same time, there are conflicting reports as to whether elevation of calpastatin, an endogenous calpain inhibitor, alters pathology. We compared the effects of pharmacological calpain inhibition in the mdx mouse using leupeptin and a proprietary compound (C101) that linked the inhibitory portion of leupeptin to carnitine (to increase uptake into muscle). Administration of C101 for 4 wk did not improve muscle histology, function, or serum creatine kinase levels in mdx mice. Mdx mice injected daily with leupeptin (36 mg/kg) for 6 mo also failed to show improved muscle function, histology, or creatine kinase levels. Biochemical analysis revealed that leupeptin administration caused an increase in m-calpain autolysis and proteasome activity, yet calpastatin levels were similar between treated and untreated mdx mice. These data demonstrate that pharmacological inhibition of calpain is not a promising intervention for the treatment of Duchenne muscular dystrophy due to the ability of skeletal muscle to counter calpain inhibitors by increasing multiple degradative pathways.
Authors:
Joshua Selsby; Klara Pendrak; Monica Zadel; Zuozhen Tian; Jennifer Pham; Ted Carver; Pedro Acosta; Elisabeth Barton; H Lee Sweeney
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-09-15
Journal Detail:
Title:  American journal of physiology. Regulatory, integrative and comparative physiology     Volume:  299     ISSN:  1522-1490     ISO Abbreviation:  Am. J. Physiol. Regul. Integr. Comp. Physiol.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-11-03     Completed Date:  2010-12-01     Revised Date:  2013-10-22    
Medline Journal Info:
Nlm Unique ID:  100901230     Medline TA:  Am J Physiol Regul Integr Comp Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  R1192-201     Citation Subset:  IM    
Affiliation:
Department of Physiology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Biological Markers / blood
Calcium-Binding Proteins / metabolism
Calpain / antagonists & inhibitors*,  metabolism
Creatine Kinase / blood
Cysteine Proteinase Inhibitors / pharmacology*
Diaphragm / drug effects*,  enzymology,  pathology,  physiopathology
Disease Models, Animal
Dose-Response Relationship, Drug
Genotype
Leupeptins / pharmacology*
Mice
Mice, Inbred mdx
Muscle Contraction / drug effects
Muscle Strength / drug effects
Muscular Dystrophy, Duchenne / drug therapy*,  enzymology,  physiopathology
Necrosis
Phenotype
Proteasome Endopeptidase Complex / metabolism
Time Factors
Grant Support
ID/Acronym/Agency:
AR053461/AR/NIAMS NIH HHS; F32-AR-055005-01/AR/NIAMS NIH HHS; U54-AR052646/AR/NIAMS NIH HHS
Chemical
Reg. No./Substance:
0/Biological Markers; 0/Calcium-Binding Proteins; 0/Cysteine Proteinase Inhibitors; 0/Leupeptins; 79079-11-1/calpastatin; EC 2.7.3.2/Creatine Kinase; EC 3.4.22.-/Calpain; EC 3.4.25.1/Proteasome Endopeptidase Complex; J97339NR3V/leupeptin
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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