A mathematical model to quantify RYR Ca(2+) leak and associated heat production in resting human skeletal muscle fibers

Cycling of Ca(2+) between the sarcoplasmic reticulum (SR) and myoplasm is an important component of skeletal muscle resting metabolism. As part of this cycle, Ca(2+) leaks from the SR into the myoplasm and is pumped back into the SR using ATP, which leads to the consumption of O(2) and generation of heat. Ca(2+) may leak through release channels or ryanodine receptors (RYRs). RYR Ca(2+) leak can be monitored in a skinned fiber preparation in which leaked Ca(2+) is pumped into the t-system and measured with a fluorescent dye. However, accurate quantification faces a number of hurdles. To overcome them, we developed a mathematical model of Ca(2+) movement in these preparations. The model incorporated Ca(2+) pumps that move Ca(2+) from the myoplasm to the SR and from the junctional space (JS) to the t-system, Ca(2+) buffering by EGTA in the JS and myoplasm and by buffers in the SR, and Ca(2+) leaks from the SR into the JS and myoplasm and from the t-system into the myoplasm. The model accurately simulated Ca(2+) uptake into the t-system, the relationship between myoplasmic [Ca(2+)] and steady-state t-system [Ca(2+)], and the effect of blocking RYR Ca(2+) leak on t-system Ca(2+) uptake. The magnitude of the leak through the RYRs would contribute ∼5% of the resting heat production of human muscle. In normal resting fibers, RYR Ca(2+) leak makes a small contribution to resting metabolism. RYR-focused pathologies have the potential to increase RYR Ca(2+) leak and the RYR leak component of resting metabolism.