Upregulation of the CaV 1.1-ryanodine receptor complex in a rat model of critical illness myopathy

Am J Physiol Regul Integr Comp Physiol. 2011 Jun;300(6):R1384-91. doi: 10.1152/ajpregu.00032.2011. Epub 2011 Apr 6.


The processes that trigger severe muscle atrophy and loss of myosin in critical illness myopathy (CIM) are poorly understood. It has been reported that muscle disuse alters Ca(2+) handling by the sarcoplasmic reticulum. Since inactivity is an important contributor to CIM, this finding raises the possibility that elevated levels of the proteins involved in Ca(2+) handling might contribute to development of CIM. CIM was induced in 3- to 5-mo-old rats by sciatic nerve lesion and infusion of dexamethasone for 1 wk. Western blot analysis revealed increased levels of ryanodine receptor (RYR) isoforms-1 and -2 as well as the dihydropyridine receptor/voltage-gated calcium channel type 1.1 (DHPR/Ca(V) 1.1). Immunostaining revealed a subset of fibers with elevation of RYR1 and Ca(V) 1.1 that had severe atrophy and disorganization of sarcomeres. These findings suggest increased Ca(2+) release from the sarcoplasmic reticulum may be an important contributor to development of CIM. To assess the endogenous functional effects of increased intracellular Ca(2+) in CIM, proteolysis of α-fodrin, a well-known target substrate of Ca(2+)-activated proteases, was measured and found to be 50% greater in CIM. There was also selective degradation of myosin heavy chain relative to actin in CIM muscle. Taken together, our findings suggest that increased Ca(2+) release from the sarcoplasmic reticulum may contribute to pathology in CIM.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calcium / metabolism
  • Caveolin 1 / metabolism*
  • Critical Illness*
  • Denervation
  • Dexamethasone / adverse effects
  • Disease Models, Animal
  • Female
  • Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / metabolism
  • Muscular Atrophy / metabolism
  • Muscular Diseases / chemically induced
  • Muscular Diseases / metabolism*
  • Myosins / metabolism
  • Rats
  • Rats, Wistar
  • Ryanodine Receptor Calcium Release Channel / metabolism*
  • Sarcoplasmic Reticulum / metabolism
  • Sciatic Nerve / surgery
  • Up-Regulation / physiology*


  • Cav1 protein, rat
  • Caveolin 1
  • Kcnma1 protein, rat
  • Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
  • Ryanodine Receptor Calcium Release Channel
  • Dexamethasone
  • Myosins
  • Calcium