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This Article Full Text Full Text (PDF) All Versions of this Article: 583/2/767    most recent jphysiol.2007.138024v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Paolini, C. Articles by Protasi, F. Search for Related Content PubMed PubMed Citation Articles by Paolini, C. Articles by Protasi, F. Related Collections Skeletal Muscle and Exercise

¹ IIM Interuniversity Institute of Myology, Ce.S.I. Centro Scienze dell'Invecchiamento, University G. d'Annunzio, I-66013 Chieti Italy
² IIM Interuniversity Institute of Myology, Department of Anatomy and Physiology, University of Padova, I-35131 Padova Italy
³ IIM Interuniversity Institute of Myology, Department of Biomedical Sciences, University of Padova, I-35131 Padova Italy
⁴ Department of Anaesthesia Research, Brigham and Women's Hospital, 02115 Boston MA

Calsequestrin (CS), the major Ca²⁺-binding protein in the sarcoplasmic reticulum (SR), is thought to play a dual role in excitation–contraction coupling: buffering free Ca²⁺ increasing SR capacity, and modulating the activity of the Ca²⁺ release channels (RyRs). In this study, we generated and characterized the first murine model lacking the skeletal CS isoform (CS1). CS1-null mice are viable and fertile, even though skeletal muscles appear slightly atrophic compared to the control mice. No compensatory increase of the cardiac isoform CS2 is detectable in any type of skeletal muscle. CS1-null muscle fibres are characterized by structural and functional changes, which are much more evident in fast-twitch muscles (EDL) in which most fibres express only CS1, than in slow-twitch muscles (soleus), where CS2 is expressed in about 50% of the fibres. In isolated EDL muscle, force development is preserved, but characterized by prolonged time-to-peak and half-relaxation time, probably related to impaired calcium release from and re-uptake by the SR. Ca²⁺-imaging studies show that the amount of Ca²⁺ released from the SR and the amplitude of the Ca²⁺ transient are significantly reduced. The lack of CS1 also causes significant ultrastructural changes, which include: (i) striking proliferation of SR junctional domains; (ii) increased density of Ca²⁺-release channels (confirmed also by ³H-ryanodine binding); (iii) decreased SR terminal cisternae volume; (iv) higher density of mitochondria. Taken together these results demonstrate that CS1 is essential for the normal development of the SR and its calcium release units and for the storage and release of appropriate amounts of SR Ca²⁺.

(Received 8 June 2007; accepted after revision 5 July 2007; first published online 12 July 2007)
Corresponding author F. Protasi: CeSI, Center of Research on Aging, Università degli Studi G. d'Annunzio, I-66013 Chieti, Italy. Email: fprotasi{at}unich.it

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