Myogenic vector expression of insulin-like growth factor I stimulates muscle cell differentiation and myofiber hypertrophy in transgenic mice.
The avian skeletal alpha-actin gene was used as a template for construction of a myogenic expression vector that was utilized to direct expression of a human IGF-I cDNA in cultured muscle cells and in striated muscle of transgenic mice. The proximal promoter region, together with the first intron and 1.8 kilobases of 3'-noncoding flanking sequence of the avian skeletal alpha-actin gene directed high level expression of human insulin-like growth factor I (IGF-I) in stably transfected C2C12 myoblasts and transgenic mice. Expression of the actin/IGF-I hybrid gene in C2C12 muscle cells increased levels of myogenic basic helix-loop-helix factor and contractile protein mRNAs and enhanced myotube formation. Expression of the actin/IGF-I hybrid gene in mice elevated IGF-I concentrations in skeletal muscle 47-fold resulting in myofiber hypertrophy. IGF-I concentrations in serum and body weight were not increased by transgene expression, suggesting that the effects of transgene expression were localized. These results indicate that sustained overexpression of IGF-I in skeletal muscle elicits myofiber hypertrophy and provides the basis for manipulation of muscle physiology utilizing skeletal alpha-actin-based vectors.
Coleman
M E
ME
Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
DeMayo
F
F
Yin
K C
KC
Lee
H M
HM
Geske
R
R
Montgomery
C
C
Schwartz
R J
RJ
D000199:Actins / Q000235:genetics*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002459:Cell Fusion; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D005813:Genes, Synthetic; D005822:Genetic Vectors; D018257:Helix-Loop-Helix Motifs; D006984:Hypertrophy; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000473:pathology*; D009124:Muscle Proteins / Q000096:biosynthesis / Q000235:genetics; D009132:Muscles / Q000166:cytology*; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis*; D014162:Transfection
D000199:Actins; D009124:Muscle Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D007334:Insulin-Like Growth Factor I