Utrophin is a calpain substrate in muscle cells

Calpains are Ca2+‐dependent cytosolic cysteine proteases that participate in the pathology of Duchenne muscular dystrophy (DMD). Utrophin is a functional homolog of dystrophin that partially compensates for dystrophin deficiency in myofibers of mdx mice. In this study, we investigated the susceptibi...

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Bibliographic Details
Published in:Muscle & nerve 2006-06, Vol.33 (6), p.753-759
Main Authors: Courdier-Fruh, Isabelle, Briguet, Alexandre
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
calpain
Calpain - antagonists & inhibitors
Calpain - isolation & purification
Calpain - metabolism
Cells, Cultured
cleavage
Diseases of striated muscles. Neuromuscular diseases
Duchenne muscular dystrophy
Enzyme Inhibitors - pharmacology
Fundamental and applied biological sciences. Psychology
Gene Expression
Humans
In Vitro Techniques
Ionophores - pharmacology
Kidney - cytology
Medical sciences
Mice
Muscle Cells - enzymology
Muscle Fibers, Skeletal - enzymology
Muscle, Skeletal - cytology
Muscular Dystrophy, Duchenne - metabolism
Muscular Dystrophy, Duchenne - pathology
Neurology
Striated muscle. Tendons
Substrate Specificity
utrophin
Utrophin - genetics
Utrophin - metabolism
Vertebrates: osteoarticular system, musculoskeletal system
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Summary:Calpains are Ca2+‐dependent cytosolic cysteine proteases that participate in the pathology of Duchenne muscular dystrophy (DMD). Utrophin is a functional homolog of dystrophin that partially compensates for dystrophin deficiency in myofibers of mdx mice. In this study, we investigated the susceptibility of utrophin to cleavage by calpain in vitro and in muscle cells. We found that utrophin is a direct in vitro substrate of purified calpain I and II. Cleavage of utrophin by calpain I or II generates specific degradation products that are also found in cultured control and DMD myotubes under conditions with elevated intracellular Ca2+ levels. In addition, we showed that activation of cellular calpains by Ca2+ ionophore treatment reduces utrophin protein levels in muscle cells and that calpain inhibition prevents this Ca2+‐induced reduction in utrophin levels. These observations suggest that, beside its known effect on general muscle protein degradation, calpain contributes to DMD pathology by specifically degrading the compensatory protein utrophin. Muscle Nerve, 2006
ISSN:0148-639X
1097-4598
DOI:10.1002/mus.20549