Upregulation of the CaV1.1-ryanodine receptor complex in a rat model of critical illness myopathy
- 1 June 2011
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Regulatory, Integrative and Comparative Physiology
- Vol. 300 (6), R1384-R1391
- https://doi.org/10.1152/ajpregu.00032.2011
Abstract
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 Ca2+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 Ca2+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/CaV1.1). Immunostaining revealed a subset of fibers with elevation of RYR1 and CaV1.1 that had severe atrophy and disorganization of sarcomeres. These findings suggest increased Ca2+release from the sarcoplasmic reticulum may be an important contributor to development of CIM. To assess the endogenous functional effects of increased intracellular Ca2+in CIM, proteolysis of α-fodrin, a well-known target substrate of Ca2+-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 Ca2+release from the sarcoplasmic reticulum may contribute to pathology in CIM.Keywords
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