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

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. Calcium influx through the Ca v 1.1 channel initiates skeletal muscle contractions. Zorzato and colleagues report a role for the proteins JP45 and calsequestrin in strengthening skeletal muscle contraction by modulating Ca v 1.1 channel activity.