Fast skeletal muscle troponin activator CK‐2066260 mitigates skeletal muscle weakness independently of the underlying cause

摘要: Background Muscle weakness is a common symptom in numerous diseases and regularly occurring problem associated with ageing. Prolonged low-frequency force depression (PLFFD) form of exercise-induced skeletal muscle observed after exercise. Three different intramuscular mechanisms underlying PLFFD have been identified: decreased sarcoplasmic reticulum Ca2+ release, myofibrillar sensitivity, dysfunction. We here used these three forms as models to study the effectiveness fast troponin activator, CK-2066260, mitigate weakness. Methods Experiments were performed on intact single fibres or fibre bundles from mouse flexor digitorum brevis, which stimulated electrical current pulses, while free cytosolic [Ca2+ ] ([Ca2+ ]i ) measured. was induced by stimulation protocols: (i) repeated isometric contractions at low intensity (350 ms tetani given every 5 s for 100 contractions); (ii) high (250 0.5 300 (iii) eccentric 20% length increase 20 10 contractions). The extent cause assessed comparing force-[Ca2+ relationship (30 Hz) (120 frequencies before (control) 30 min induction PLFFD, an additional rest presence CK-2066260 (10 μM). Results following low-intensity high-intensity fatiguing predominantly due release respectively. exposure resulted marked increases Hz 52 ± 16% 151 13% 6 4% 98 40% controls contractions, Following mainly dysfunction, it not fully reversed increasing 48 8% 76 6% control. Conclusions activator effectively mitigates weakness, especially when caused impaired activation contractile machinery either reduced sensitivity.