Molecular and cellular defects of skeletal muscle in an animal model of acute quadriplegic myopathy.
Muscle denervation and concomitant high-dose dexamethasone treatment in rodents produces characteristic pathologic features of severe muscle atrophy and selective myosin heavy filament (MyHC) depletion, identical to those seen in acute quadriplegic myopathy (AQM), also known as critical illness myopathy. We tested the hypothesis that defective pre-translational processes contribute to the atrophy and selective MyHC depletion in this model. We examined the effects of combined glucocorticoid-denervation treatment on MyHC and actin mRNA populations; we also studied mRNA expression of the myogenic regulatory factors (MRFs), primary transcription factors for MyHC. Adult female rats were subjected to proximal sciatic denervation followed by high-dose dexamethasone (DD) treatment (5 mg/kg body weight daily) for 7 days. Disease controls included rats treated with denervation alone (DN) or dexamethasone alone (DX). At 1 week the plantaris atrophied by approximately 42% in DD muscles. DD treatment resulted in selective MyHC protein depletion; actin protein concentration was not significantly changed. Despite an increase in total RNA concentration in DN and DD muscles, MyHC and actin mRNA concentrations were significantly decreased in these muscles. MyHC mRNA showed a significantly more extensive depletion relative to actin mRNA in DD muscles. Glucocorticoid treatment did not influence a denervation-induced increase in the mRNA expression of the MRFs. We conclude that a deleterious interaction between glucocorticoid and denervation treatments in skeletal muscle is responsible for pre-translational defects that reduce actin and MyHC mRNA substrates in a disproportionate fashion. The resultant selective MyHC depletion contributes to the severe muscle atrophy.
Mozaffar
Tahseen
T
Department of Neurology, University of California, Irvine, 101 City Drive South, Building 22C, Route 13, Orange, California 92868, USA. mozaffar@uci.edu
Haddad
Fadia
F
Zeng
Ming
M
Zhang
Li Ying
LY
Adams
Greg R
GR
Baldwin
Kenneth M
KM
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000208:Acute Disease; D000818:Animals; D003907:Dexamethasone / Q000633:toxicity; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D009121:Muscle Denervation; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D009133:Muscular Atrophy / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D009135:Muscular Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000172:deficiency / Q000235:genetics; D011115:Polyneuropathies / Q000378:metabolism / Q000503:physiopathology; D011782:Quadriplegia / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
D000199:Actins; D009124:Muscle Proteins; D018006:Myogenic Regulatory Factors; D012333:RNA, Messenger; D003907:Dexamethasone; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; D018995:Myosin Heavy Chains