title: Impaired Ca(2+) release contributes to muscle weakness in a rat model of critical illness myopathy.
abstract: 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.
authors: Department of Physiology & Pharmacology, Karolinska Institutet, von Eulers väg, 8, 2 floor, Stockholm, 171 77, Sweden.
authors: Monica
authors: M
authors: Llano-Diez
authors: Department of Physiology & Pharmacology, Karolinska Institutet, von Eulers väg, 8, 2 floor, Stockholm, 171 77, Sweden.
authors: Arthur J
authors: AJ
authors: Cheng
authors: Department of Physiology & Pharmacology, Karolinska Institutet, von Eulers väg, 8, 2 floor, Stockholm, 171 77, Sweden.
authors: William
authors: W
authors: Jonsson
authors: Department of Physiology & Pharmacology, Karolinska Institutet, von Eulers väg, 8, 2 floor, Stockholm, 171 77, Sweden.
authors: Niklas
authors: N
authors: Ivarsson
authors: Department of Physiology & Pharmacology, Karolinska Institutet, von Eulers väg, 8, 2 floor, Stockholm, 171 77, Sweden.
authors: Håkan
authors: H
authors: Westerblad
authors: Department of Physiology & Pharmacology, Karolinska Institutet, von Eulers väg, 8, 2 floor, Stockholm, 171 77, Sweden.
authors: Vic
authors: V
authors: Sun
authors: Department of Physiology & Pharmacology, Karolinska Institutet, von Eulers väg, 8, 2 floor, Stockholm, 171 77, Sweden.
authors: Nicola
authors: N
authors: Cacciani
authors: Department of Physiology & Pharmacology, Karolinska Institutet, von Eulers väg, 8, 2 floor, Stockholm, 171 77, Sweden.
authors: Lars
authors: L
authors: Larsson
authors: Department of Physiology & Pharmacology, Karolinska Institutet, von Eulers väg, 8, 2 floor, Stockholm, 171 77, Sweden. joseph.bruton@ki.se.
authors: Joseph
authors: J
authors: Bruton
mesh_terms: D000818:Animals; D016638:Critical Illness; D004195:Disease Models, Animal; D004492:Edetic Acid / Q000600:supply & distribution*; D005260:Female; D008297:Male; D009119:Muscle Contraction / Q000502:physiology; D053580:Muscle Strength / Q000502:physiology*; D018908:Muscle Weakness / Q000503:physiopathology*; D009135:Muscular Diseases / Q000139:chemically induced* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D004492:Edetic Acid
keywords: Ca2+ handling; Critical illness myopathy; Excitation-contraction coupling; Intensive care unit; Skeletal muscle weakness