Altered expression of genes regulating skeletal muscle mass in the portacaval anastomosis rat.
We examined the temporal relationship between portacaval anastomosis (PCA), weight gain, changes in skeletal muscle mass and molecular markers of protein synthesis, protein breakdown, and satellite cell proliferation and differentiation. Male Sprague-Dawley rats with end to side PCA (n=24) were compared with sham-operated pair-fed rats (n=24). Whole body weight, lean body mass, and forelimb grip strength were determined at weekly intervals. The skeletal muscle expression of the ubiquitin proteasome system, myostatin, its receptor (the activin 2B receptor) and its signal, cyclin-dependent kinase inhibitor (CDKI) p21, insulin-like growth factor (IGF)-I and its receptor (IGF-I receptor-alpha), and markers of satellite cell proliferation and differentiation were quantified. PCA rats did not gain body weight and had lower lean body mass, forelimb grip strength, and gastrocnemius muscle weight. The skeletal muscle expression of the mRNA of ubiquitin proteasome components was higher in PCA rats in the first 2 wk followed by a lower expression in the subsequent 2 wk (P<0.01). The mRNA and protein of myostatin, activin 2B receptor, and CDKI p21 were higher, whereas IGF-I and its receptor as well as markers of satellite cell function (proliferating nuclear cell antigen, myoD, myf5, and myogenin) were lower at weeks 3 and 4 following PCA (P < 0.05). We conclude that PCA resulted in uninhibited proteolysis in the initial 2 wk. This was followed by an adaptive response in the later 2 wk consisting of an increased expression of myostatin that may have contributed to reduced muscle protein synthesis, impaired satellite cell function, and lower skeletal muscle mass.
Dasarathy
Srinivasan
S
Department of Gastroenterology, Cleveland Clinic, Lerner Research Institute and the Cleveland Clinic Lerner College of Medicine, NE40, 9500 Euclid Ave., Cleveland, OH 44195, USA. dasaras@ccf.org
Muc
Sean
S
Hisamuddin
Kola
K
Edmison
John M
JM
Dodig
Milan
M
McCullough
Arthur J
AJ
Kalhan
Satish C
SC
D030301:Activin Receptors, Type II / Q000235:genetics / Q000378:metabolism; D000596:Amino Acids / Q000097:blood; D000818:Animals; D001823:Body Composition; D001835:Body Weight; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D016207:Cytokines / Q000097:blood; D015870:Gene Expression; D006728:Hormones / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism; D009929:Organ Size; D011167:Portacaval Shunt, Surgical / Q000009:adverse effects*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors
D000596:Amino Acids; D018797:Cell Cycle Proteins; D016207:Cytokines; D006728:Hormones; D009124:Muscle Proteins; D018006:Myogenic Regulatory Factors; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B; D046988:Proteasome Endopeptidase Complex