Muscle-specific inactivation of the IGF-I receptor induces compensatory hyperplasia in skeletal muscle.
During the development of skeletal muscle, myoblasts withdraw from the cell cycle and differentiate into myotubes. The insulin-like growth factors IGF-I and IGF-II, through their cognate tyrosine kinase receptor (IGF-I receptor), are known to play a role in this process. After withdrawal of myoblasts from the cell cycle, IGF-I promotes muscle differentiation by inducing the expression or activity of myogenic regulatory factors (MyoD, myogenin) and effectors (p21). However, little is known about the intracellular mechanisms by which the IGF-I system regulates these factors during the process of myogenesis. Here we show that MKR mice, which express a dominant negative IGF-I receptor specifically in skeletal muscle, have marked muscle hypoplasia from birth to 3 weeks of age. This hypoplasia occurs concomitantly with a decrease in ERK immunoreactivity levels and decreases in MyoD and myogenin expression. BrdU immunocytochemistry showed a compensatory hyperplasia as MKR mice grew to adulthood. Interestingly, hyperplasia occurred concomitantly with an increase in p38, MyoD, myogenin, and p21 immunoreactivity levels, as well as a decrease in Twist levels. These findings suggest that regulation of these cellular elements by IGF-I may play a role in the development and differentiation of skeletal muscle in vivo.
Fernández
Ana M
AM
Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Dupont
Joëlle
J
Farrar
Roger P
RP
Lee
Sukho
S
Stannard
Bethel
B
Le Roith
Derek
D
D000818:Animals; D000831:Animals, Newborn; D005260:Female; D006130:Growth Disorders / Q000235:genetics / Q000473:pathology; D006801:Humans; D006965:Hyperplasia; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology*; D017570:MyoD Protein / Q000235:genetics; D018008:Myogenin / Q000235:genetics; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D015854:Up-Regulation
C503799:MYOG protein, human; D017570:MyoD Protein; C503801:Myog protein, mouse; D018008:Myogenin; D017526:Receptor, IGF Type 1