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  • Increased myoplasmic inorganic phosphate (Pi) has been suggested to have an important role in skeletal muscle fatigue, especially in the early phase. In the present study we used intact fast-twitch muscle cells from mice completely deficient in creatine kinase (CK-/-) to test this suggestion. These CK-/- muscle cells provide a good model since they display a higher Pi concentration in the unfatigued state and fatigue without significant increase of Pi.

  • Tetanic contractions (350 ms duration) were produced in intact single muscle fibres. The free myoplasmic [Ca2+] ([Ca2+]i) was measured with the fluorescent indicator indo-1. The force-[Ca2+]i relationship was constructed from tetani at different frequencies.

  • Compared with wild-type fibres, CK-/- fibres displayed lower force in 100 Hz tetani and at saturating [Ca2+]i (i.e. 100 Hz stimulation during caffeine exposure), higher tetanic [Ca2+]i during the first 100 ms of tetanic stimulation, reduced myofibrillar Ca2+ sensitivity when measurements were performed 100–200 ms into tetani, and slowed force relaxation that was due to altered cross-bridge kinetics rather than delayed Ca2+ removal from the myoplasm.

  • In wild-type fibres, a series of 10 tetani resulted in reduced tetanic force, slowed force relaxation, and increased amplitude of [Ca2+]i tails after tetani. None of these changes were observed in CK-/- fibres.

  • Complementary experiments on isolated fast-twitch extensor digitorum longus muscles showed a reduction of tetanic force and relaxation speed in CK-/- muscles similar to those observed in single fibres.

  • In conclusion, increased Pi concentration can explain changes observed in the early phase of skeletal muscle fatigue. Increased Pi appears to be involved in both fatigue-induced changes of cross-bridge function and SR Ca2+ handling.