title: Upregulation of the CaV 1.1-ryanodine receptor complex in a rat model of critical illness myopathy.
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 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.
authors.affiliation: Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, Ohio, USA.
authors.forename: Susan D
authors.initials: SD
authors.lastname: Kraner
authors.forename: Qingbo
authors.initials: Q
authors.lastname: Wang
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Novak
authors.forename: Dongmei
authors.initials: D
authors.lastname: Cheng
authors.forename: David R
authors.initials: DR
authors.lastname: Cool
authors.forename: Junmin
authors.initials: J
authors.lastname: Peng
authors.forename: Mark M
authors.initials: MM
authors.lastname: Rich
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism*; D016638:Critical Illness; D003714:Denervation; D003907:Dexamethasone / Q000009:adverse effects; D004195:Disease Models, Animal; D005260:Female; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000378:metabolism; D009133:Muscular Atrophy / Q000378:metabolism; D009135:Muscular Diseases / Q000139:chemically induced / Q000378:metabolism*; D009218:Myosins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D012584:Sciatic Nerve / Q000601:surgery; D015854:Up-Regulation / Q000502:physiology*
chemical_list: C495537:Cav1 protein, rat; D051242:Caveolin 1; C494842:Kcnma1 protein, rat; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D019837:Ryanodine Receptor Calcium Release Channel; D003907:Dexamethasone; D009218:Myosins; D002118:Calcium