Proposed model for NAC-mediated prevention of heat- and halothane-induced rhabdomyolysis in CASQ1-null mice. Schematic model proposing a series of events linking SR Ca²⁺ leak (step 1) to rhabdomyolysis during heat or halothane exposure (step 6) in muscle from CASQ1-null mice. Resting Ca²⁺ leak and oxidative stress are slightly increased (compared with WT) in mice lacking CASQ1 (shown as orange junctional Ca²⁺ ions). During exposure to heat or halothane, SR Ca²⁺ leak (shown as additional purple junctional Ca²⁺ ions) and oxidative stress (steps 1 and 2) are further increased, driving a feed-forward mechanism (step 3²⁶ ) that ultimately leads to SR Ca²⁺ store depletion (step 4^22,53 ), activation of SOCE (step 5²⁴ ), and uncontrolled Ca²⁺ influx resulting in severe contractures and rhabdomyolysis (steps 6 and 7¹⁹ ). The protective effects of NAC and Trolox shown in this study likely result from direct effects of the antioxidants to reduce oxidative stress, thus blocking the feed-forward mechanism (steps 3 to 5) leading to SOCE activation. CASQ1-null = calsequestrin-1 knockout; DHPR = dihydropyridine receptor; NAC = N-acetylcysteine; RYR1 = ryanodine receptor type-1; SERCA-1 = sarco/endoplasmic reticulum Ca²⁺-ATPase-1; SOCE = store operated Ca²⁺ entry; SR = sarcoplasmic reticulum; WT = wild type.