Malignant Hyperthermia (MH) and Central Core Disease (CCD) are related skeletal diseases often linked to the ryanodine receptor (RYR1) gene. Calsequestrin (CASQ1) is the main Ca²⁺ buffer of the Sarcoplasmic Reticulum, also proposed as modulator of RYR1 function. We have recently discovered that CASQ1- knockout mice develop a MH-like phenotype. To collect further information on the possible contribution of CASQ1 to myopathies, we studied fast-twitch muscles from CASQ1-null mice (birth to 4m and older than 1y) using structural, functional, and molecular approaches. The maturation of the excitation-contraction (EC) apparatus seems to be delayed/impaired, i.e. longitudinal and peripheral junctions are frequent, RyRs are arranged in multiple rows, etc. CASQ1 deficiency also results in mild atrophy in adult due to reduction in fiber diameter (EDL weight: 0.026±0.04 g vs 0.033±0.04 g); and loss of force (grip test: 0,031±0,006 g/N vs. 0,066±0,012 g/N). Microarray profiling of FDB muscles from 4m old CASQ1-null mice shows disregulation of genes involved in protein degradation, i.e. CathepsinL and Atrogin1 are over-expressed. With age, fibers from CASQ1-null mice also develop structural alterations which are reminiscent of core myopathies. These findings CASQ1 is important for post-natal maturation of the EC coupling apparatus and suggest a possible involvement in core myopathies.