Key result
High-frequency conditioning stimulation potentiates low-frequency force ~30%, driven by increased myofibrillar Ca2+ sensitivity.
This study demonstrates that low-frequency force potentiation following high-frequency stimulation in human skeletal muscle is primarily driven by an intramuscular increase in myofibrillar Ca2+ sensitivity rather than central mechanisms.
Hypothesis-generating for muscle potentiation mechanisms; leaves open translation to clinical or cardiac outcomes.
Electrically-evoked low-frequency (submaximal) force is increased immediately following high-frequency stimulation in human skeletal muscle. Although central mechanisms have been suggested to be the major cause of this low-frequency force potentiation, intramuscular factors might contribute. Thus, we hypothesized that two intramuscular Ca2+-dependent mechanisms can contribute to the low-frequency force potentiation: increased sarcoplasmic reticulum Ca2+ release and increased myofibrillar Ca2+ sensitivity. Experiments in humans were performed on the plantar flexor muscles at a shortened, intermediate, and long muscle length, and electrically evoked contractile force and membrane excitability (i.e., M-wave amplitude) were recorded during a stimulation protocol. Low-frequency force potentiation was assessed by stimulating with a low-frequency tetanus (25 Hz, 2 s duration), followed by a high-frequency tetanus (100 Hz, 2 s duration), and finally followed by another low-frequency tetanus (25 Hz, 2 s duration) tetanus. Similar stimulation protocols were performed on intact mouse single fibres from flexor digitorum brevis muscle, whereby force and myoplasmic free [Ca2+] ([Ca2+]i) were assessed. Our data show a low-frequency force potentiation that was not muscle length-dependent in human muscle and it was not accompanied by any increase in M-wave amplitude. A length-independent low-frequency force potentiation could be replicated in mouse single fibres, supporting an intramuscular mechanism. We show that at physiological temperature (31°C) this low-frequency force potentiation in mouse fibres corresponded with an increase in sarcoplasmic reticulum (SR) Ca2+. When mimicking the slower contractile properties of human muscle by cooling mouse single fibres to 18°C, the low-frequency force potentiation was accompanied by minimally increased SR Ca2+ release and hence it could be explained by increased myofibrillar Ca2+ sensitivity. Finally, introducing a brief 200 ms pause between the high- and low-frequency tetanus in human and mouse muscle revealed that the low-frequency force potentiation is abolished, arguing that increased myofibrillar Ca2+ sensitivity is the main intramuscular mechanism underlying the low-frequency force potentiation in humans.
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Cheng et al. (2017) studied Healthy (n=11). High-frequency conditioning stimulation vs. Pre-conditioning baseline was evaluated on Low-frequency (25 Hz) force potentiation (p=<0.05). High-frequency conditioning stimulation induced a length-independent low-frequency force potentiation of approximately 30% in human plantar flexors, primarily driven by increased myofibrillar Ca2+ sensitivity.
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