Elsevier

Experimental Neurology

Volume 76, Issue 1, April 1982, Pages 121-138
Experimental Neurology

Calcium-mediated myopathy at neuromuscular junctions of normal and dystrophic muscle

https://doi.org/10.1016/0014-4886(82)90106-6Get rights and content

Abstract

Previous studies showed that a myopathy which can be produced in vertebrate muscle by inactivating esterases is mimicked by exposure to carbamylcholine and requires agonist-receptor interaction and extracellular calcium. A most consistent aspect of the myopathy is dissolution of Z-disks in myofibrils near the postsynaptic membrane. Using mouse extensor digitorum longus (EDL) muscles in vitro, we found that leupeptin partially protects the Z-disks from dissolution. Chloroquine had much less, if any, effect. These data are compatible with the suggestion that prolonged agonist action at the neuromuscular junction results in the activation of the calcium-activated protease known to destroy the Z-disk protein. Because dystrophic mouse muscles reportedly have increased activities of calcium-activated proteases, we compared the response of normal and dystrophic EDL muscle. These muscles showed no significant difference after 3 h in Krebs baths, but when carbachol was added, there was a significantly greater amount of Z-disk damage in dystrophic muscles than in muscles from wild types (129 ReJ) or from albino mice. As in normal muscle, the agonist-induced myopathy in dystrophic muscle is both calcium- and protease dependent.

References (56)

  • M.K. Reddy et al.

    Removal of Z-lines and α-actinin from isolated myofibrils by a calcium-activated neutral protease

    J. Biol. Chem.

    (1975)
  • W.T. Stauber et al.

    Inhibition of lysosomal function in red and white skeletal muscles by chloroquine

    Exp. Neurol.

    (1981)
  • T. Toyo-Oka et al.

    Inhibition of proteolytic activity of calcium-activated neutral protease by leupeptin and antipain

    Biochem. Biophys. Res. Commun.

    (1978)
  • L. Wecker et al.

    Paraoxon-induced myopathy: muscle specificity and acetylcholine involvement

    Exp. Neurol.

    (1976)
  • I.B. Wilson et al.

    Carbamylation of acetylcholinesterase

    J. Biol. Chem.

    (1960)
  • T. Aoyagi et al.

    Structures and activities of protease inhibitors of microbial origin

  • A.Th. Ariens et al.

    Reversible necrosis at the end-plate region in striated muscles of the rat poisoned with cholinesterase inhibitors

    Experientia

    (1969)
  • J.W.L. Bird

    Skeletal muscle lysosomes

  • J. Bodensteiner et al.

    Intracellular calcium accumulation in Duchenne dystrophy and other myopathies: a study of 567,000 muscle fibers in 114 biopsies

    Neurology (New York)

    (1978)
  • W.A. Busch et al.

    Ca++ specific removal of Z-lines from rabbit skeletal muscle

    J. Cell. Biol.

    (1972)
  • H.W. Chalkley

    Method for quantitative morphologic analysis of tissues

    J. Natl. Cancer Inst.

    (1943)
  • W.R. Dayton et al.

    Some properties of a Ca++-activated protease that may be involved in myofibrillar protein turnover

  • W.R. Dayton et al.

    A Ca++-activated protease possibly involved in myofibrillar protein turnover. Purification from porcine muscle

    Biochemistry

    (1976)
  • W.R. Dayton et al.

    A Ca++-activated protease possibly involved in myofibrillar protein turnover. Partial characterization of the purified enzyme

    Biochemistry

    (1976)
  • W.R. Dayton et al.

    Localization of a Ca2+-activated neutral protease in skeletal muscle

    J. Cell Biol.

    (1980)
  • A.G. Engel et al.

    Study of long-term anticholinesterase therapy effects on neuromuscular transmission and on motor end-plate fine structure

    Neurology (New York)

    (1973)
  • A. Enomoto et al.

    Therapeutic trials in muscular dystrophy. III. Studies of microbial proteinase inhibitors in murine dystrophy

    Arch. Neurol.

    (1977)
  • G.M. Fenichel et al.

    Chronic inhibition of cholinesterase as a cause of myopathy

    Neurology (New York)

    (1972)
  • Cited by (0)

    1

    This study was supported by two grants from the National Institutes of Health, NS09315 and GM 10422. The authors thank Mary Johnson and Marie Read for technical assistance and Steve Jones and Bruce Land for helpful advice.

    View full text