Abstract
Mutations of Ca2+-activated proteases (calpains) cause muscular dystrophies. Nevertheless, the specific role of calpains in Ca2+ signalling during the onset of dystrophies remains unclear. We investigated Ca2+ handling in skeletal cells from calpain 3-deficient mice. [Ca2+]i responses to caffeine, a ryanodine receptor (RyR) agonist, were decreased in −/− myotubes and absent in −/− myoblasts. The −/− myotubes displayed smaller amplitudes of the Ca2+ transients induced by cyclopiazonic acid in comparison to wild type cells. Inhibition of L-type Ca2+ channels (LCC) suppressed the caffeine-induced [Ca2+]i responses in −/− myotubes. Hence, the absence of calpain 3 modifies the sarcoplasmic reticulum (SR) Ca2+ release, by a decrease of the SR content, an impairment of RyR signalling, and an increase of LCC activity. We propose that calpain 3-dependent proteolysis plays a role in activating support proteins of intracellular Ca2+ signalling at a stage of cellular differentiation which is crucial for skeletal muscle regeneration.
Highlights
Calpains are intracellular nonlysosomal cysteine proteases whose functions are regulated by Ca2+
We propose that calpain 3-dependent proteolysis plays a role in activating support proteins of intracellular Ca2+ signalling at a stage of cellular differentiation which is crucial for skeletal muscle regeneration
It was demonstrated that the absence of the skeletal muscle specific calpain 3 causes limb girdle muscular dystrophy type 2A (LGMD2A) [4], a disease that has been linked to a significant level of apoptotic fibres [5]
Summary
Calpains are intracellular nonlysosomal cysteine proteases whose functions are regulated by Ca2+ (see [1] for review). These proteins display one Ca2+-binding domain on each of the large and small subunits [2]. The physiological roles of the calpains are not yet fully understood but as proteases, they may regulate important cellular functions. Calpains have been shown to play regulatory roles in other cells, International Journal of Cell Biology in which they can influence gene expression through the cleavage of specific transcription factors, affecting cell viability by controlling apoptosis, and modulating other cell processes through the cleavage of specific kinases and ion channels (reviewed by Carafoli and Molinari; [3]). The pathological process due to calpain 3 deficiency is associated with alterations in membrane permeability [6] suggesting the possible existence of a perturbation in homeostasis, especially in the intracellular Ca2+ concentration ([Ca2+]i) during muscular dystrophy
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