Autocrine growth factor signaling by insulin-like growth factor-II mediates MyoD-stimulated myocyte maturation.
Skeletal muscle differentiation, maturation, and regeneration are regulated by interactions between intrinsic genetic programs controlled by myogenic transcription factors, including members of the MyoD and MEF2 families, and environmental cues mediated by hormones and growth factors. Insulin-like growth factors (IGFs) also play key roles in muscle development, and in the maintenance and repair of mature muscle, but their mechanisms of interaction with other muscle regulatory networks remain undefined. To evaluate the potential interplay between MyoD and IGF signaling pathways, we have studied muscle differentiation in C3H 10T1/2 fibroblasts acutely converted to myoblasts by quantitative infection with a recombinant adenovirus encoding mouse MyoD. In these cells, IGF-II gene and protein expression are induced as early events in differentiation, and the IGF-I receptor and downstream signaling molecules, including Akt, are rapidly activated. Interference with IGF-II production by a tetracycline-inhibited adenovirus expressing an IGF-II cDNA in the antisense orientation reversibly inhibited both production of muscle-specific structural proteins and myocyte fusion to form multinucleated myotubes. Similar results were achieved with a tetracycline-inhibited adenovirus expressing dominant-negative Akt. Our observations identify a robust autocrine amplification network in which MyoD enhances the later steps in muscle differentiation by induction of a locally acting growth factor.
Wilson
Elizabeth M
EM
Molecular Medicine Division, Oregon Health & Science University, Portland, Oregon 97239-3098, USA.
Hsieh
Marlene M
MM
Rotwein
Peter
P
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002454:Cell Differentiation; D018076:DNA, Complementary / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005799:Genes, Dominant; D006133:Growth Substances / Q000378:metabolism*; D015151:Immunoblotting; D007150:Immunohistochemistry; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D032342:Muscle Cells / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D009132:Muscles / Q000166:cytology; D017570:MyoD Protein / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012313:RNA / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D015398:Signal Transduction; D013752:Tetracycline / Q000494:pharmacology; D013997:Time Factors
D018076:DNA, Complementary; D006133:Growth Substances; D017570:MyoD Protein; D011518:Proto-Oncogene Proteins; D017527:Receptor, IGF Type 2; D012313:RNA; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D013752:Tetracycline