Jgp_201711763 297..300

Fast-twitch skeletal muscles are specialized for in vivo motor functions that require high power (mastication and load lifting), high speed (eyelid blink), or a combination of the two (withdrawal reflexes and escape responses). Those functions that rely on high power often involve tetanic stimulation of the effector muscles, resulting in sustained force generation even during tetani that are not fused, which is the physiological norm (McMahon, 1984; Biewener, 2016). Taking escape responses as an example, there is a clear adaptive advantage to rapid initiation of a forceful ballistic contraction, which to a degree is achieved by expression of skeletal muscle myosin isoforms that exhibit fast or super-fast turnover rates in their interactions with actin (Rome and Lindstedt, 1998; Hoh, 2002). Rapid delivery of Ca to the myoplasm during excitation–contraction coupling is another mechanism that would presumably speed the rate of force development and contribute to an early increase in the ability of the muscle to generate power. Mechanisms such as these are energetically expensive and are thus evident to lesser degrees in slow-twitch skeletal muscles. They are also regulated properties of cardiac and most smooth muscles, in which Ca delivery is modulated by neural activity and circulating levels of cardioactive and vasoactive hormones. In this issue, Bakker et al. examine the mechanism underlying the observation that a short burst of high-frequency action potentials at the onset of tetany results in a greater rate of force development. Previous studies of the initial stages of contraction have shown that tetanic contractions of fast-twitch motor units in both rodents and humans begin with a high-frequency train of two or three action potentials before settling into a lower frequency of continued stimulation (studies cited in the present paper by Bakker et al. [2017]). Although this might be the response of an under-damped neural control system or a system of more complex design, long-standing work by several groups (review by Binder-Macleod and Kesar [2005] cited by Bakker et al. [2017]) has shown that this initial burst of action potentials contributes to the rate of force development in fast-twitch skeletal muscles. Imposing two or three higher frequency action potentials at the beginning of tetanic stimulation significantly increases the rate of rise of force, a phenomenon that has been thought to be caused by increased release of Ca from the sarcoplasmic reticulum. A study by Cheng et al. (2013), using the Ca-sensitive dye indo-1, suggested that a pair of high-frequency action potentials at the beginning of a lower-frequency tetanus evoked an initial Ca transient of significantly greater amplitude. Such an increase would explain the faster rate of rise of force associated with the initial doublet of higher-frequency stimuli and was believed by the authors to be caused by greater Ca release from the sarcoplasmic reticulum in response to the second stimulus. The present study by Bakker et al. (2017) further examines the mechanism by which an initial short burst of action potentials alters the time course of intracellular Ca in ways that might explain a faster rise of force observed under these same conditions. In this instance, the authors used the Ca indicator Mag-Fluo-4, which is faster and has lower affinity than indicators used in previous studies, and laser-scanning microscopy to achieve greater temporal resolution in recordings of intracellular Ca concentration during tetanic stimulation. Their results, which are systematic, elegant, and convincing, go a long way toward resolving the basis for the observed greater increase in initial Ca concentration caused by insertion of a doublet of high-frequency action potentials. With the greater time resolution achieved with the combination of Ca indicator and recording system used, the authors observe that the amplitude of the Ca transient in response to the second stimulus of the doublet is actually less than the first. However, the sustained myoplasmic Ca concentration between the first and second stimuli of the doublet is significantly greater than seen when the stimulus frequency during the initial phase is lower, i.e., just sufficient to achieve a fused tetanic contraction. Both the shorter interval and the higher levels of Ca between successive Ca transients, in response to the higher-frequency doublet, can account for the apparently greater increase in ini-