The Ca2+ spark of mammalian muscle. Physiology or pathology?

In every type of muscle it is necessary to increase [Ca2+] in the cytosol to trigger contraction, then decrease it to allow relaxation. This transient must be especially sharp and brief in fast twitch skeletal muscle, where the goal is speed. Indeed, cell-averaged Ca2+ transients reveal a time course of Ca2+ release current with rapid activation and fast closure, so that the temporal window of Ca2+ release only lasts a few milliseconds. A local event of Ca2+ release, the Ca2+ spark, also features a rapid start and a decisive termination, in similar time scales. This finding is essential to the view that sparks are elementary responses containing the main features of the global signal. This view has been clouded by various findings. Sparks were first found in cardiac ventricle, a muscle that prizes modulation over speed. They are abundant in skeletal muscle of the frog, but not in mammals, where their spontaneous production decreases abruptly during postnatal development (Chun et al. 2003). In the frog their frequency and duration can be controlled by membrane depolarization. By contrast depolarization in cut mammalian fibres only causes embers, resulting from opening of single ryanodine receptor (RyR) channels (Csernoch et al. 2004). (By comparison with these embers it seems safe to conclude that sparks of mammalian muscle involve opening of many channels.) In 2002, Felder and Franzini-Armstrong showed a structural underpinning for the differences. In addition to the usual RyR channels of isoform 1 (RyR1) at the junction with transverse tubules, the sarcoplasmic reticulum of frogs (and fish and birds) has RyR3 channels in a lateral, para-junctional position. These may be the main generators of sparks. Mammalian muscle instead has only junctional channels, of isoform 1. Although RyR1 can produce sparks, special treatments are necessary. Permeabilization or removal of the plasma membrane helps (Kirsch et al. 2001), suggesting that the loss of a factor (or a function) enables spark production. Natalia Shirokova and colleagues have now contributed two incisive studies of the conditions that promote them. Isaeva & Shirokova (2003) first suggested that degradation of mitochondrial metabolism, leading to a reduction in redox potential, could be the proximate cause of appearance of sparks after membrane permeabilization. In this issue of The Journal of Physiology, Isaeva et al. (2005) buttress this claim, by comparing the appearance of sparks in cells with different mitochondrial content or metabolic substrates. Furthermore, they propose that sparks appear when reactive oxygen species, known promoters of RyR channel opening, increase their concentration in the cytosol as the redox potential falls upon impairment of mitochondrial function. (This may not be the sole mediator, as in many other tissues mitochondria are known to take up Ca2+, thereby tempering ER Ca2+ signalling.) This view of sparks as response to stress is generally consistent with the recent report (Wang et al. 2005) of two manoeuvres that induce sparks in intact mouse muscle fibres, strenuous exercise and hypotonic shock. These and other observations link skeletal muscle Ca2+ signalling and the vast field of studies of interactions between Ca2+ stores (ER/SR) and mitochondria. While most studies in muscle stress the reactive role of mitochondria (they take up Ca2+ as a way to monitor and adjust to contractile activity), the newest works strengthen the possibility that mitochondria may also condition Ca2+ signalling, by either maintaining a reducing environment or taking up Ca2+ (analogous to their ‘firewall’ role in pancreatic cells, Tinel et al. 1999). Where does this leave Ca2+ sparks? The distances that Ca2+ must travel to reach its target are shorter in mammalian muscle, which has two triad junctions per sarcomere, than in fish or frogs, which have one. Hence, during normal function there may be no need in mammals for the highly interactive, metabolically costly and intrinsically explosive spark modality of channel activation. Questions remain. Are the sparks, induced by exercise or otherwise, an unintended consequence of higher metabolic activity – a problem – or a valuable adaptation? Are there other conditions, including fatigue and disease, under which Ca2+ sparks have a functional role? We now know that these questions cannot be answered without addressing, and controlling for, the role of mitochondria.