Figure 9

Proposed pathogenic model for myopathy in CASQ1-null mice. 1) CASQ1-null fibers exhibit elevated resting Ca²⁺ levels at body temperature [29], likely caused by increased RYR1 Ca²⁺ leak and/or enhanced SOCE [58,59]. 2) High cytoplasmic-resting Ca²⁺ increases the demand for ATP required to drive SERCA-mediated SR Ca²⁺ reuptake. 3) Increases in Ca²⁺ and energy demand enhance PGC-1α expression and, thus, mitochondrial biogenesis. 4-5) Increased metabolic rate and mitochondrial content enhance mSOF production and oxidative stress, which, over time, leads to mitochondrial damage. 6) Chronic exposure of fibers to high Ca²⁺ and oxidative stress results in formation of core-like regions (that is, myopathy). The central role of enhanced oxidative stress as a requisite step in this pathogenic model is supported by the demonstration that NAC treatment reduces mitochondrial damage and improves muscle function. Ca²⁺, calcium ions; CASQ1, skeletal isoform of calsequestrin; SR, sarcoplasmic reticulum; GSH/GSSG, reduced and oxidized glutathione; mSOF, mitochondrial superoxide flashes; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; RYR1, ryanodine receptor type-1; SOCE, store-operated Ca²⁺ entry; WT, wild type; NAC, N-acetylcysteine.