Skeletal muscle atrophy is associated with an increased expression of myostatin and impaired satellite cell function in the portacaval anastamosis rat.
Proliferation and differentiation of satellite cells are critical in the regeneration of atrophied muscle following immobilization and aging. We hypothesized that impaired satellite cell function is responsible for the atrophy of skeletal muscle also seen in cirrhosis. Myostatin and insulin-like growth factor 1 (IGF1) have been identified to be positive and negative regulators, respectively, of satellite cell function. Using a rat model of cirrhosis [portacaval anastamosis (PCA)] and sham-operated controls, we examined the expression of myostatin, its receptor activinR2b, and its downstream messenger cyclin-dependent kinase inhibitor p21 (CDKI p21) as well as IGF1 and its receptor in the gastrocnemius muscle. Expression of PCNA, a marker of proliferation, and myogenic regulatory factors (myoD, myf5, and myogenin), markers of differentiation of satellite cells, were also measured. Real- time PCR for mRNA and Western blot assay for protein quantification were performed. PCA rats had lower body weight and gastrocnemius weight compared with sham animals (P < 0.05). PCNA and myogenic regulatory factors were lower in PCA rats (P < 0.05). Myostatin, activinR2b, and CDKI p21 were higher in the PCA animals (P < 0.05). The expression of IGF1 and its receptor was lower in liver and skeletal muscle of PCA animals (P < 0.05). These data suggest that skeletal muscle atrophy seen in the portacaval shunted rats is a consequence of impaired satellite cell proliferation and differentiation mediated, in part, by higher myostatin and lower IGF1 expression.
Dasarathy
Srinivasan
S
Schwartz Center for Metabolism and Nutrition, Department of Medicine, Division of Gastroenterology, Case Western Reserve University, MetroHealth Medical Center, Cleveland OH 44109, USA. sxd28@case.edu
Dodig
Milan
M
Muc
Sean M
SM
Kalhan
Satish C
SC
McCullough
Arthur J
AJ
D000818:Animals; D000911:Antibodies, Monoclonal; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D017931:DNA Primers; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis; D008106:Liver Cirrhosis, Experimental / Q000473:pathology*; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis; D009133:Muscular Atrophy / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000096:biosynthesis; D018995:Myosin Heavy Chains / Q000096:biosynthesis; D055435:Myostatin; D009929:Organ Size / Q000502:physiology; D011167:Portacaval Shunt, Surgical; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D032496:Satellite Cells, Skeletal Muscle / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*; D025801:Ubiquitin / Q000378:metabolism
D000911:Antibodies, Monoclonal; D017931:DNA Primers; C525913:Mstn protein, rat; D009124:Muscle Proteins; D018006:Myogenic Regulatory Factors; D055435:Myostatin; D016212:Transforming Growth Factor beta; D025801:Ubiquitin; D007334:Insulin-Like Growth Factor I; D046988:Proteasome Endopeptidase Complex; D018995:Myosin Heavy Chains