Abstract
Mitochondria are both the primary provider of ATP and the pivotal regulator of cell death, which are essential for physiological muscle activities. Ca(2+) plays a multifaceted role in mitochondrial function. During muscle contraction, Ca(2+) influx into mitochondria activates multiple enzymes related to tricarboxylic acid (TCA) cycle and oxidative phosphorylation, resulting in increased ATP synthesis to meet the energy demand. Pathophysiological conditions such as skeletal muscle denervation or unloading also lead to elevated Ca(2+) levels inside mitochondria. However, the outcomes of this steady-state elevation of mitochondrial Ca(2+) level include exacerbated reactive oxygen species (ROS) generation, sensitized opening of mitochondrial permeability transition pore (mPTP), induction of programmed cell death, and ultimately muscle atrophy. Previously, both acute and long-term endurance exercises have been reported to activate certain signaling pathways to counteract ROS production. Meanwhile, electrical stimulation is known to help prevent apoptosis and alleviate muscle atrophy in denervated animal models and patients with motor impairment. There are various mechanistic studies that focus on the excitation-transcription coupling framework to understand the beneficial role of exercise and electrical stimulation. Interestingly, a recent study has revealed an unexpected role of rapid mitochondrial Ca(2+) transients in keeping mPTP at a closed state with reduced mitochondrial ROS production. This discovery motivated us to contribute this review article to inspire further discussion about the potential mechanisms underlying differential outcomes of physiological mitochondrial Ca(2+) transients and pathological mitochondrial Ca(2+) elevation in skeletal muscle ROS production.