Schematic representation of a skeletal muscle cell and of Ca²⁺ and Na⁺ ion fluxes across the sarcolemma and sarcoplasmic reticulum (SR). Activation of Cav1.1 by membrane depolarization causes the RyR1 channel to open and to release Ca²⁺ from SR, thus triggering muscle contraction. Ca²⁺ concentration is regulated by the Ca²⁺-ATPase membrane pump (SERCA) that sequesters Ca²⁺ in the SR and by the Na⁺-K⁺-ATPase membrane pump and the Ca²⁺-Na⁺ antiport that exchange Ca²⁺ for Na⁺ across the sarcolemma. Regulation of calcium flux may be disrupted at any of these sites. ATP depletion, by consumption during muscle contraction, or reduced ATP production, results in intracellular Ca²⁺ increasing, muscle contraction, and continued energy consumption, leading to rhabdomyolysis.