No human myopathies have been yet associated with mutations of Calsequestrin-1 (CASQ1), the main Ca²⁺ buffer of the sarcoplasmic reticulum (SR). However, deletion of CASQ1 results in increased susceptibility of CASQ1-null mice to trigger lethal malignant hyperthermia (MH) episodes. Since MH and central core disease (CCD, a myopathy characterized by presence of cores lacking mitochondrial activity) often co-exist in humans, we investigated whether CASQ1-null mice develop a myopathy in EDL muscles of adult (4–6 months) and older (14–31 months) animals. In adult mice, lack of CASQ1 is accompanied by a) increased expression of PCG-1a (involved in mitochondriogenesis), b) significant increase in mitochondrial volume, and c) increased oxidative stress (measured as content of GSSG and relative GSH/GSSG ratio). With age (14–31 months) CASQ1-null mice display a significant decrease in force output and a progressive structural decay of skeletal fibers (25–55%) visible as loss of cross striation and presence of areas of excessive contracture and/or degeneration). At this stage, PGC-1a expression is significantly decreased compared to WT and most mitochondria present sign of swelling and structural damage. Volume of mitochondria is reduced in those areas presenting more severe structural decay. This pathological phenotype closely resemble that of other models of MH/CCD, and is likely started by mitochondrial proliferation and excessive oxidative stress.