Enhanced dihydropyridine receptor calcium channel activity restores muscle strength in JP45/CASQ1 double knockout mice

Barbara Mosca, Osvaldo Delbono, Maria Laura Messi, Leda Bergamelli, Zhong-Min Wang, Mirko Vukcevic, Ruben Lopez, Susan Treves, Miyuki Nishi, Hiroshi Takeshima, Cecilia Paolini, Marta Martini, Giorgio Rispoli, Feliciano Protasi and Francesco Zorzato ()
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Barbara Mosca: General Pathology section, University of Ferrara
Osvaldo Delbono: Wake Forest University School of Medicine
Maria Laura Messi: Wake Forest University School of Medicine
Leda Bergamelli: General Pathology section, University of Ferrara
Zhong-Min Wang: Wake Forest University School of Medicine
Mirko Vukcevic: Basel University Hospital
Ruben Lopez: Basel University Hospital
Susan Treves: General Pathology section, University of Ferrara
Miyuki Nishi: Graduate School of Pharmacological Sciences, Kyoto University
Hiroshi Takeshima: Graduate School of Pharmacological Sciences, Kyoto University
Cecilia Paolini: University Gabriele d Annunzioof Chieti
Marta Martini: Physiology and Biophysics University of Ferrara
Giorgio Rispoli: Physiology and Biophysics University of Ferrara
Feliciano Protasi: University Gabriele d Annunzioof Chieti
Francesco Zorzato: General Pathology section, University of Ferrara

Nature Communications, 2013, vol. 4, issue 1, 1-9

Abstract: Abstract Muscle strength declines with age in part due to a decline of Ca2+ release from sarcoplasmic reticulum calcium stores. Skeletal muscle dihydropyridine receptors (Cav1.1) initiate muscle contraction by activating ryanodine receptors in the sarcoplasmic reticulum. Cav1.1 channel activity is enhanced by a retrograde stimulatory signal delivered by the ryanodine receptor. JP45 is a membrane protein interacting with Cav1.1 and the sarcoplasmic reticulum Ca2+ storage protein calsequestrin (CASQ1). Here we show that JP45 and CASQ1 strengthen skeletal muscle contraction by modulating Cav1.1 channel activity. Using muscle fibres from JP45 and CASQ1 double knockout mice, we demonstrate that Ca2+ transients evoked by tetanic stimulation are the result of massive Ca2+ influx due to enhanced Cav1.1 channel activity, which restores muscle strength in JP45/CASQ1 double knockout mice. We envision that JP45 and CASQ1 may be candidate targets for the development of new therapeutic strategies against decay of skeletal muscle strength caused by a decrease in sarcoplasmic reticulum Ca2+ content.

Date: 2013
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DOI: 10.1038/ncomms2496

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