Can inorganic phosphate explain sag during unfused tetanic contractions of skeletal muscle?

We test the hypothesis that cytosolic inorganic phosphate (P_i) can account for the contraction-induced reductions in twitch duration which impair summation and cause force to decline (sag) during unfused tetanic contractions of fast-twitch muscle. A five-state model of crossbridge cycling was used to simulate twitch and unfused tetanic contractions. As P_i concentration ([P_i]) was increased from 0 to 30 mmol·L^-1, twitch duration decreased, with progressive reductions in sensitivity to P_i as [P_i] was increased. When unfused tetani were simulated with rising [P_i], sag was most pronounced when initial [P_i] was low, and when the magnitude of [P_i] increase was large. Fast-twitch extensor digitorum longus (EDL) muscles (sag-prone, typically low basal [P_i]) and slow-twitch soleus muscles (sag-resistant, typically high basal [P_i]) were isolated from 14 female C57BL/6 mice. Muscles were sequentially incubated in solutions containing either glucose or pyruvate to create typical and low P_i environments, respectively. Twitch duration was greater (P < 0.05) in pyruvate than glucose in both muscles. Stimuli applied at intervals approximately three times the time to peak twitch tension resulted in sag of 35.0 ± 3.7% in glucose and 50.5 ± 1.4% in pyruvate in the EDL (pyruvate > glucose; P < 0.05), and 3.9 ± 0.3% in glucose and 37.8 ± 2.7% in pyruvate in the soleus (pyruvate > glucose; P < 0.05). The influence of P_i on crossbridge cycling provides a tenable mechanism for sag. Moreover, the low basal [P_i] in fast-twitch relative to slow-twitch muscle has promise as an explanation for the fiber-type dependency of sag.