Differential regulation of IGF-I and IGF-II gene expression in skeletal muscle cells.
Insulin-like growth factor (IGF)-I and IGF-II play major roles in the regulation of skeletal muscle growth and differentiation, and both are locally expressed in muscle cells. Recent studies have demonstrated that IGF-II up-regulates its own gene expression during myogenesis and this auto-regulatory loop is critical for muscle differentiation. How local IGF-I is regulated in this process is unclear. Here, we report that while IGF-II up-regulated its own gene expression, it suppressed IGF-I gene expression during myogenesis. These opposite effects of IGF-II on IGF-I and IGF-II genes expression were time dependent and dose dependent. It has been shown that IGFs activate the PI3K-Akt-mTOR, p38 MAPK, and Erk1/2 MAPK pathways. In myoblasts, we examined their role(s) in mediating the opposite effects of IGF-II. Our results showed that both the PI3K-Akt-mTOR and p38 MAPK pathways played critical roles in increasing IGF-II mRNA expression. In contrast, mTOR was required for down-regulating the IGF-I gene expression by IGF-II. In addition, Akt, Erk1/2 MAPK, and p38 MAPK pathways were also involved in the regulation of basal levels of IGF-I and IGF-II genes during myogenesis. These findings reveal a previously unrecognized negative feedback mechanism and extend our knowledge of IGF-I and IGF-II gene expression and regulation during myogenesis.
Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, People's Republic of China.
Shuang
S
Jiao
Hongxia
H
Ren
Yun
Y
Li
Jianfeng
J
Zhou
Cunming
C
Duan
Ling
L
Lu
D000818:Animals; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D025461:Feedback, Physiological; D005786:Gene Expression Regulation; D007334:Insulin-Like Growth Factor I / Q000235:genetics* / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D048049:Extracellular Signal-Regulated MAP Kinases; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C513121:IGF2 protein, mouse; C519530:insulin-like growth factor-1, mouse; C546843:mTOR protein, mouse