title: Enhanced dihydropyridine receptor calcium channel activity restores muscle strength in JP45/CASQ1 double knockout mice.
abstract: Muscle strength declines with age in part due to a decline of Ca(2+) release from sarcoplasmic reticulum calcium stores. Skeletal muscle dihydropyridine receptors (Ca(v)1.1) initiate muscle contraction by activating ryanodine receptors in the sarcoplasmic reticulum. Ca(v)1.1 channel activity is enhanced by a retrograde stimulatory signal delivered by the ryanodine receptor. JP45 is a membrane protein interacting with Ca(v)1.1 and the sarcoplasmic reticulum Ca(2+) storage protein calsequestrin (CASQ1). Here we show that JP45 and CASQ1 strengthen skeletal muscle contraction by modulating Ca(v)1.1 channel activity. Using muscle fibres from JP45 and CASQ1 double knockout mice, we demonstrate that Ca(2+) transients evoked by tetanic stimulation are the result of massive Ca(2+) influx due to enhanced Ca(v)1.1 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 Ca(2+) content.
authors: Department of Experimental and Diagnostic Medicine, General Pathology section, University of Ferrara, Via Borsari 46, Ferrara 44121, Italy.
authors: Barbara
authors: B
authors: Mosca
authors: Osvaldo
authors: O
authors: Delbono
authors: Maria
authors: M
authors: Laura Messi
authors: Leda
authors: L
authors: Bergamelli
authors: Zhong-Min
authors: ZM
authors: Wang
authors: Mirko
authors: M
authors: Vukcevic
authors: Ruben
authors: R
authors: Lopez
authors: Susan
authors: S
authors: Treves
authors: Miyuki
authors: M
authors: Nishi
authors: Hiroshi
authors: H
authors: Takeshima
authors: Cecilia
authors: C
authors: Paolini
authors: Marta
authors: M
authors: Martini
authors: Giorgio
authors: G
authors: Rispoli
authors: Feliciano
authors: F
authors: Protasi
authors: Francesco
authors: F
authors: Zorzato
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000172:deficiency* / Q000378:metabolism; D002155:Calsequestrin; D005786:Gene Expression Regulation; D066298:In Vitro Techniques; D008345:Manganese / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology; D008565:Membrane Proteins / Q000172:deficiency* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000502:physiology; D053580:Muscle Strength / Q000502:physiology*
chemical_list: C529218:CACNA1S protein, mouse; D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins; D002155:Calsequestrin; C503130:Casq1 protein, mouse; C485996:JP-45 protein, mouse; D008565:Membrane Proteins; D008345:Manganese