to the editor: We are struck by the remarkable results contained in the article by Zhang et al. (5). Put bluntly, if these results are independently verified, then a fundamental reappraisal of over four decades of muscle energetics will be required. This is because Zhang et al. (5) infer from their data that, under conditions of submaximal stimulation (at 30°C), ∼80% of the metabolic cost of contraction of isolated, fast-twitch, skeletal muscle [mouse extensor digitorum longus (EDL)] is attributable to Ca2+ pumping by the sarcoplasmic reticulum (SR), leaving only 20% to cross-bridge cycling. These values are roughly the converse of what is conventionally considered to be the economics of energy expenditure by active striated muscle. We are rather skeptical, for the following reasons.
i) An unreferenced paper by Barclay (1), which employed the same muscle preparation at a comparable temperature (25°C), demonstrated that non-cross-bridge-related heat production (estimated by extrapolating to zero filament overlap the heat produced at various degrees of stretch) was 35% and was unaltered by a fatiguing protocol that reduced force to 55% of its initial value. ii) Baylor and Hollingworth (3) showed that during tetanic stimulation of mouse EDL (67 Hz at 16°C) the amount of Ca2+ released per stimulus pulse was ∼0.08 μmol/g (this is an overestimate, because much more Ca2+ was released by the first pulse than later pulses) and was little different at 28°C. So in the 100 pulses used by Zhang et al. (5) in a 2-s tetanus, a total of 8 μmol/g Ca2+ would have been released, which would require 4 μmol/g ATP to be pumped into the SR. In comparison, Zhang et al. (5) measured the activation cost to be over fourfold greater: 15 μmol/g. iii) In another unreferenced study (4), activation heat (once again, estimated by “extrapolation”) of mouse EDL at 27°C was 35%. In the presence of a submaximal dose of dantrolene (an inhibitor of the skeletal muscle Ca2+-release channel), tetanic force was reduced to 36% of its “control” value. Nevertheless, activation heat still accounted for only 42% of the total heat liberated. iv) The idea that 20% of isometric energy turnover is due to cross-bridge cycling is incompatible with the known mechanical performance of fast-twitch muscles. If cross bridges account for only 20% of energy use, then the rate of ATP splitting per cross bridge must be one-quarter the value previously assumed. Maintenance of a high isometric force, in any cross-bridge scheme that requires a low rate of turnover, can be achieved only by reducing the rate of cross-bridge detachment. However, a low detachment rate is inconsistent with the rapid force dynamics and the flat force-velocity curve characteristic of EDL muscles (2).
Zhang et al. (5) offer no mechanistic explanation for their result but suggest that it differs from previous data due to an effect of species or temperature or as a result of using submaximal activation. Points i and iii above argue against an effect of either species or temperature, and the dantrolene experiments (point iii) counter the idea that activation costs are higher at submaximal levels of activation.
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