title: Lessons from calsequestrin-1 ablation in vivo: much more than a Ca(2+) buffer after all.
abstract: Calsequestrin type-1 (CASQ1), the main sarcoplasmic reticulum (SR) Ca(2+) binding protein, plays a dual role in skeletal fibers: a) it provides a large pool of rapidly-releasable Ca(2+) during excitation-contraction (EC) coupling; and b) it modulates the activity of ryanodine receptors (RYRs), the SR Ca(2+) release channels. We have generated a mouse lacking CASQ1 in order to further characterize the role of CASQ1 in skeletal muscle. Contrary to initial expectations, CASQ1 ablation is compatible with normal motor activity, in spite of moderate muscle atrophy. However, CASQ1 deficiency results in profound remodeling of the EC coupling apparatus: shrinkage of junctional SR lumen; proliferation of SR/transverse-tubule contacts; and increased density of RYRs. While force development during a twitch is preserved, it is nevertheless characterized by a prolonged time course, likely reflecting impaired Ca(2+) re-uptake by the SR. Finally, lack of CASQ1 also results in increased rate of SR Ca(2+) depletion and inability of muscle to sustain tension during a prolonged tetani. All modifications are more pronounced (or only found) in fast-twitch extensor digitorum longus muscle compared to slow-twitch soleus muscle, likely because the latter expresses higher amounts of calsequestrin type-2 (CASQ2). Surprisingly, male CASQ1-null mice also exhibit a marked increased rate of spontaneous mortality suggestive of a stress-induced phenotype. Consistent with this idea, CASQ1-null mice exhibit an increased susceptibility to undergo a hypermetabolic syndrome characterized by whole body contractures, rhabdomyolysis, hyperthermia and sudden death in response to halothane- and heat-exposure, a phenotype remarkably similar to human malignant hyperthermia and environmental heat-stroke. The latter findings validate the CASQ1 gene as a candidate for linkage analysis in human muscle disorders.
authors: CeSI-Center for Research on Ageing & DNI-Department of Neuroscience and Imaging, University Gabriele d’Annunzioof Chieti, Via Colle dell’Ara, 66100 Chieti, Italy. fprotasi@unich.it
authors: Feliciano
authors: F
authors: Protasi
authors: Cecilia
authors: C
authors: Paolini
authors: Marta
authors: M
authors: Canato
authors: Carlo
authors: C
authors: Reggiani
authors: Marco
authors: M
authors: Quarta
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002155:Calsequestrin / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D056966:Excitation Contraction Coupling / Q000502:physiology*; D006801:Humans; D008297:Male; D008305:Malignant Hyperthermia / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018656:Muscle Fibers, Fast-Twitch / Q000378:metabolism*; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism; D009133:Muscular Atrophy / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000235:genetics / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D002155:Calsequestrin; D002352:Carrier Proteins; C503130:Casq1 protein, mouse; D019837:Ryanodine Receptor Calcium Release Channel; C514388:casq2 protein, mouse; D002118:Calcium