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Involvement of calpains in Ca2+-induced disruption of excitation-contraction coupling in mammalian skeletal muscle fibers

Involvement of calpains in Ca2+-induced disruption of excitation-contraction coupling in... Abstract In skeletal muscle fibers, the coupling between excitation of the surface membrane and the release of Ca 2+ from the sarcoplasmic reticulum is irreversibly disrupted if cytoplasmic Ca 2+ concentration (Ca 2+ ) is raised to micromolar levels for a prolonged period. This excitation-contraction (EC) uncoupling may contribute to muscle weakness after some types of exercise and in certain muscle diseases and has been linked to structural alteration of the triad junctions, but its molecular basis is unclear. Both μ-calpain, a ubiquitous Ca 2+ -activated protease, and muscle-specific calpain-3 become autolytically activated at micromolar Ca 2+ and have been suggested to be responsible for the uncoupling. This study used controlled Ca 2+ exposure in mechanically skinned fibers from extensor digitorum longus muscle to show that EC uncoupling still occurs in muscle fibers of calpain-3-deficient mice, with a Ca 2+ dependence indistinguishable from that in normal mice and rats. Western blotting of muscle fibers that had been partially EC uncoupled by exposure to an intermediate Ca 2+ level (∼5 μM Ca 2+ for 3 min, no ATP) showed the presence of autolytic activation of a proportion of the μ-calpain present, but with little or no activation of calpain-3. Homogenates of normal and calpain-3-deficient muscles exposed to micromolar Ca 2+ displayed similar levels of diffusible proteolytic activity, as gauged by the rate of decline of passive force in stretched, skinned muscle fibers. Exogenously added μ-calpain, preactivated by elevated Ca 2+ and applied in the presence of 1 μM Ca 2+ , disrupted EC coupling in a manner similar to raised Ca 2+ . We conclude that calpain-3 is not responsible for Ca 2+ -induced disruption of EC coupling, but that μ-calpain is a plausible candidate. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png AJP - Cell Physiology The American Physiological Society

Involvement of calpains in Ca2+-induced disruption of excitation-contraction coupling in mammalian skeletal muscle fibers

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Publisher
The American Physiological Society
Copyright
Copyright © 2010 the American Physiological Society
ISSN
0363-6143
eISSN
1522-1563
DOI
10.1152/ajpcell.00008.2009
pmid
19295178
Publisher site
See Article on Publisher Site

Abstract

Abstract In skeletal muscle fibers, the coupling between excitation of the surface membrane and the release of Ca 2+ from the sarcoplasmic reticulum is irreversibly disrupted if cytoplasmic Ca 2+ concentration (Ca 2+ ) is raised to micromolar levels for a prolonged period. This excitation-contraction (EC) uncoupling may contribute to muscle weakness after some types of exercise and in certain muscle diseases and has been linked to structural alteration of the triad junctions, but its molecular basis is unclear. Both μ-calpain, a ubiquitous Ca 2+ -activated protease, and muscle-specific calpain-3 become autolytically activated at micromolar Ca 2+ and have been suggested to be responsible for the uncoupling. This study used controlled Ca 2+ exposure in mechanically skinned fibers from extensor digitorum longus muscle to show that EC uncoupling still occurs in muscle fibers of calpain-3-deficient mice, with a Ca 2+ dependence indistinguishable from that in normal mice and rats. Western blotting of muscle fibers that had been partially EC uncoupled by exposure to an intermediate Ca 2+ level (∼5 μM Ca 2+ for 3 min, no ATP) showed the presence of autolytic activation of a proportion of the μ-calpain present, but with little or no activation of calpain-3. Homogenates of normal and calpain-3-deficient muscles exposed to micromolar Ca 2+ displayed similar levels of diffusible proteolytic activity, as gauged by the rate of decline of passive force in stretched, skinned muscle fibers. Exogenously added μ-calpain, preactivated by elevated Ca 2+ and applied in the presence of 1 μM Ca 2+ , disrupted EC coupling in a manner similar to raised Ca 2+ . We conclude that calpain-3 is not responsible for Ca 2+ -induced disruption of EC coupling, but that μ-calpain is a plausible candidate.

Journal

AJP - Cell Physiology – The American Physiological Society

Published: May 1, 2009

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