Sarcoplasmic reticulum calcium uptake and speed of relaxation are depressed in nebulin-free skeletal muscle

Coen A C Ottenheijm, Chi Fong, Peter Vangheluwe, Frank Wuytack, Gopal J. Babu, Muthu Periasamy, Christian C. Witt, Siegfried Labeit, Hendrikus "Henk" Granzier

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Abstract

Previous work suggested that altered Ca2+ homeostasis might contribute to dysfunction of nebulinfree muscle, as gene expression analysis revealed that the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)-inhibitor sarcolipin (SLN) is up-regulated >70-fold in nebulin knockout mice, and here we tested this proposal. We investigated SLN protein expression in nebulin-free and wild-type skeletal muscle, as well as expression of other Ca2+-handling proteins. Ca2+ uptake capacity was determined in isolated sarcoplasmic reticulum vesicles and in intact myofibers by measuring Ca2+ transients. Muscle contractile performance was determined in skinned muscle activated with exogenous Ca2+, as well as in electrically stimulated intact muscle. We found profound up-regulation of SLN protein in nebulin-free skeletal muscle, whereas expression of other Ca 2+-handling proteins was not (calsequestrin and phospholamban) or was minimally (SERCA) affected. Speed of Ca2+ uptake was >3-fold decreased in sarcoplasmic reticulum vesicles isolated from nebulin-free muscle as well as in nebulin-free intact myofibers. Ca2+-activated stress in skinned muscle and stress produced by intact nebulin-free muscle were reduced to a similar extent compared with wild type. Half-relaxation time was significantly longer in nebulin-free compared with wild-type muscle. Thus, the present study demonstrates for the first time that nebulin might also be involved in physiological Ca2+ handling of the SR-myofibrillar system.

Original languageEnglish (US)
Pages (from-to)2912-2919
Number of pages8
JournalFASEB Journal
Volume22
Issue number8
DOIs
Publication statusPublished - Aug 2008

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Keywords

  • Muscle contractility
  • Nebulin KO model
  • Sarcolipin
  • SERCA function

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

Ottenheijm, C. A. C., Fong, C., Vangheluwe, P., Wuytack, F., Babu, G. J., Periasamy, M., ... Granzier, H. H. (2008). Sarcoplasmic reticulum calcium uptake and speed of relaxation are depressed in nebulin-free skeletal muscle. FASEB Journal, 22(8), 2912-2919. https://doi.org/10.1096/fj.07-104372