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Differential regulation of IGF-I and IGF-II gene expression in skeletal muscle cells

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Abstract

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.

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Acknowledgments

We thank Perry Zong and Elizabeth Devries, University of Michigan, for proofreading this manuscript. This work was supported by Natural Scientific Foundation of China (30928021 and 30972238), program for New Century Excellent Talents in University of Chinese Ministry of Education (NCET-10-0723), and US National Science Foundation Grants IOB-0543018 and IOS-1051034.

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Authors and Affiliations

  1. 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 Jiao, Yun Li, Jianfeng Zhou & Ling Lu

  2. Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI, 48109, USA

    Hongxia Ren & Cunming Duan

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  1. Shuang Jiao
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  2. Hongxia Ren
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  3. Yun Li
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  4. Jianfeng Zhou
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  5. Cunming Duan
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  6. Ling Lu
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Correspondence to Ling Lu.

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Supplementary Table S1. Forward and reverse primer sequence (5’-3’) for each gene1 (TIFF 70 kb)

11010_2012_1479_MOESM2_ESM.tif

Supplementary Fig. S1 Effect of insulin and IGF-I on IGF-II and IGF-I abundance during myogenesisC2C12 myoblasts were incubated with 100 ng/ml insulin (a, b) or 300 ng/ml IGF-II (c, d) for 24 h. Total RNA was extracted. IGF-II mRNA (a, c) and IGF-I mRNA (b, d) levels were measured by qRT-PCR. Values are expressed relative to 0 ng/ml growth factor treatment for both IGF-II and IGF-I after normalization to cyclophilin mRNA. *, P < 0.05; **, P < 0.01; ***, P < 0.001.2 (TIFF 126 kb)

11010_2012_1479_MOESM3_ESM.tif

Supplementary Fig. S2 Western blot testing of the efficacy of the inhibitors and overexpression vectors C2C12 cells were serum-starved for 1 h, then treated with 20 μM LY294002 (a), 200 nM rapamycin (c, d), 10 μM U0126 (e) or 20 μM SB203580 (f) for 1 h and incubated with IGF-II for 15 min. Cell lysates were collected and analyzed by western immunoblotting using specific antibodies. For overexpression experiments, C2C12 cells were transfected with myrAkt (b) or ca-mTOR (d). 24 h after transfection, C2C12 cells were serum-starved for 6 h and then incubated with IGF-II for 15 min. Cell lysates were collected and analyzed by Western blot using specific antibodies. (TIFF 621 kb)

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Jiao, S., Ren, H., Li, Y. et al. Differential regulation of IGF-I and IGF-II gene expression in skeletal muscle cells. Mol Cell Biochem 373, 107–113 (2013). https://doi.org/10.1007/s11010-012-1479-4

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  • DOI: https://doi.org/10.1007/s11010-012-1479-4

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