Key result
Muscle fibers from ICU rats had 80% lower tetanic [Ca2+]i and produced only 15% of the force seen in sham-operated rats, suggesting impaired sarcoplasmic reticulum Ca2+ release contributes to muscle weakness.
Why the study?
Does an ICU model of sedation, paralysis, and mechanical ventilation impair Ca2+ release and contribute to muscle weakness in rats?
Does an ICU model of sedation, paralysis, and mechanical ventilation impair Ca2+ release and contribute to muscle weakness in rats?
Effect estimate: 80% lower tetanic [Ca2+]i and 85% lower force
p-value: p=<0.05
In a rat model of critical illness myopathy, impaired sarcoplasmic reticulum Ca2+ release and reduced RyR and SERCA1 expression contribute to severe muscle weakness.
Impaired SR Ca2+ release may contribute to ICU weakness; leaves open whether targeting excitation-contraction coupling improves patient outcomes.
BACKGROUND: Critical illness myopathy is an acquired skeletal muscle disorder with severe myosin loss and muscle weakness frequently seen in intensive care unit (ICU) patients. It is unknown if impaired excitation-contraction coupling contributes to the muscle weakness. METHODS: We used a unique ICU model where rats were deeply sedated, post-synaptically pharmacologically paralyzed, mechanically ventilated and closely monitored for up to ten days. Single intact fibers from the flexor digitorum brevis muscle were isolated and used to measure force and free myoplasmic [Ca(2+)] ([Ca(2+)]i) during tetanic contractions. RESULTS: Fibers from ICU rats had 80 % lower tetanic [Ca(2+)]i and produced only 15 % of the force seen in fibers from sham-operated (SHAM) rats. In the presence of 5 mM caffeine, tetanic [Ca(2+)]i was similar in fibers from ICU and SHAM rats but force was 50 % lower in fibers from ICU rats than SHAM rats. Confocal imaging showed disrupted tetanic [Ca(2+)]i transients in fibers from ICU rats compared to SHAM rats. Western blots showed similar levels of Na(+) channel and dihydropyridine receptor (DHPR) protein expression, whereas ryanodine receptor (RyR) and sarco-endoplasmic reticulum Ca(2+) ATPase 1 (SERCA1) expression was markedly lower in muscle of ICU rats than in SHAM rats. Immunohistochemical analysis showed that distribution of Na(+) channel and DHPR protein on the sarcolemma was disrupted in fibers from ICU rats compared with SHAM rats. CONCLUSIONS: These results suggest that impaired SR Ca(2+) release contributes to the muscle weakness seen in patients in ICU.
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Llano‐Diez et al. (2016) studied Critical illness myopathy (n=15). Intensive care unit (ICU) simulation (sedation, paralysis, mechanical ventilation) vs. Sham-operated rats was evaluated on Tetanic [Ca2+]i and specific force in flexor digitorum brevis muscle fibers (80% lower tetanic [Ca2+]i and 85% lower force, p=<0.05). Muscle fibers from ICU rats had 80% lower tetanic [Ca2+]i and produced only 15% of the force seen in sham-operated rats, suggesting impaired sarcoplasmic reticulum Ca2+ release contributes to muscle weakness.
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