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IGF-II-mediated downregulation of peroxisome proliferator-activated receptor-γ coactivator-1α in myoblast cells involves PI3K/Akt/FoxO1 signaling pathway

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Abstract

Insulin-like growth factor II (IGF-II) can stimulate myogenesis and is critically involved in skeletal muscle differentiation. The presence of negative regulators of this process, however, is not well explored. Here, we showed that in myoblast cells, IGF-II negatively regulated peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) mRNA expression, while constitutive expression of PGC-1α induced myoblast differentiation. These results suggest that the negative regulation of PGC-1α by IGF-II may act as a negative feedback mechanism in IGF-II-induced myogenic differentiation. Reporter assays demonstrated that IGF-II suppresses the basal PGC-1α promoter activity. Blocking the IGF-II signaling pathway increased the endogenous PGC-1α levels. In addition, pharmacological inhibition of PI3 kinase activity prevented the downregulation of PGC-1α but the activation of mTOR was not required for this process. Importantly, further analysis showed that forkhead transcription factor FoxO1 contributes to mediating the effects of IGF-II on PGC-1 promoter activity. These findings indicate that IGF-II reduces PGC-1α expression in skeletal muscle cells through a mechanism involving PI3K–Akt–FoxO1 but not p38 MAPK or Erk1/2 MAPK pathways.

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References

  1. Buckingham M (2001) Skeletal muscle formation in vertebrates. Curr Opin Genet Dev 11:440–448

    Article  CAS  PubMed  Google Scholar 

  2. Zanou N, Gailly P (2013) Skeletal muscle hypertrophy and regeneration: interplay between the myogenic regulatory factors (MRFs) and insulin-like growth factors (IGFs) pathways. Cell Mol Life Sci 70:4117–4130

    Article  CAS  PubMed  Google Scholar 

  3. Duan C, Ren H, Gao S (2010) Insulin-like growth factors (IGFs), IGF receptors, and IGF-binding proteins: roles in skeletal muscle growth and differentiation. Gen Comp Endocrinol 167:344–351

    Article  CAS  PubMed  Google Scholar 

  4. Bois PR, Grosveld GC (2003) FKHR (FOXO1a) is required for myotube fusion of primary mouse myoblasts. EMBO J 22:1147–1157

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hribal ML, Nakae J, Kitamura T, Shutter JR, Accili D (2003) Regulation of insulin-like growth factor-dependent myoblast differentiation by Foxo forkhead transcription factors. J Cell Biol 162:535–541

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Erbay E, Park IH, Nuzzi PD, Schoenherr CJ, Chen J (2003) IGF-II transcription in skeletal myogenesis is controlled by mTOR and nutrients. J Cell Biol 163:931–936

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Norrbom J, Sundberg CJ, Ameln H, Kraus WE, Jansson E, et al (2004) PGC-1α mRNA expression is influenced by metabolic perturbation in exercising human skeletal muscle. J Appl Physiol (1985) 96: 189–194.

    Article  CAS  Google Scholar 

  8. Arany Z, Foo SY, Ma Y, Ruas JL, Bommi-Reddy A et al (2008) HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1α. Nature 451:1008–1012

    Article  CAS  PubMed  Google Scholar 

  9. Zechner C, Lai L, Zechner JF, Geng T, Yan Z et al (2010) Total skeletal muscle PGC-1 deficiency uncouples mitochondrial derangements from fiber type determination and insulin sensitivity. Cell Metab 12:633–642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ling C, Poulsen P, Carlsson E, Ridderstrale M, Almgren P et al (2004) Multiple environmental and genetic factors influence skeletal muscle PGC-1α and PGC-1beta gene expression in twins. J Clin Invest 114:1518–1526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Jiao S, Ren H, Li Y, Zhou J, Duan C et al (2012) Differential regulation of IGF-I and IGF-II gene expression in skeletal muscle cells. Mol Cell Biochem 373:107–113

    Article  PubMed  Google Scholar 

  12. Attias-Geva Z, Bentov I, Ludwig DL, Fishman A, Bruchim I et al (2011) Insulin-like growth factor-I receptor (IGF-IR) targeting with monoclonal antibody cixutumumab (IMC-A12) inhibits IGF-I action in endometrial cancer cells. Eur J Cancer 47:1717–1726

    Article  CAS  PubMed  Google Scholar 

  13. Ren H, Yin P, Duan C (2008) IGFBP-5 regulates muscle cell differentiation by binding to IGF-II and switching on the IGF-II auto-regulation loop. J Cell Biol 182:979–991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Herzig S, Long F, Jhala US, Hedrick S, Quinn R et al (2001) CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature 413:179–183

    Article  CAS  PubMed  Google Scholar 

  15. Remels AH, Langen RC, Schrauwen P, Schaart G, Schols AM, et al. (2009) Regulation of mitochondrial biogenesis during myogenesis. Mol Cell Endocrinol 315: 113–120.

    Article  PubMed  Google Scholar 

  16. Daitoku H, Yamagata K, Matsuzaki H, Hatta M, Fukamizu A (2003) Regulation of PGC-1 promoter activity by protein kinase B and the forkhead transcription factor FKHR. Diabetes 52:642–649

    Article  CAS  PubMed  Google Scholar 

  17. Cook SA, Matsui T, Li L, Rosenzweig A (2002) Transcriptional effects of chronic Akt activation in the heart. J Biol Chem 277:22528–22533

    Article  CAS  PubMed  Google Scholar 

  18. Rommel C, Bodine SC, Clarke BA, Rossman R, Nunez L et al (2001) Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways. Nat Cell Biol 3:1009–1013

    Article  CAS  PubMed  Google Scholar 

  19. Willett M, Cowan JL, Vlasak M, Coldwell MJ, Morley SJ (2009) Inhibition of mammalian target of rapamycin (mTOR) signalling in C2C12 myoblasts prevents myogenic differentiation without affecting the hyperphosphorylation of 4E-BP1. Cell Signal 21:1504–1512

    Article  CAS  PubMed  Google Scholar 

  20. Handschin C, Kobayashi YM, Chin S, Seale P, Campbell KP et al (2007) PGC-1α regulates the neuromuscular junction program and ameliorates Duchenne muscular dystrophy. Genes Dev 21:770–783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sandri M, Lin J, Handschin C, Yang W, Arany ZP et al (2006) PGC-1α protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proc Natl Acad Sci USA 103:16260–16265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Leone TC, Lehman JJ, Finck BN, Schaeffer PJ, Wende AR et al (2005) PGC-1α deficiency causes multi-system energy metabolic derangements: muscle dysfunction, abnormal weight control and hepatic steatosis. PLoS Biol 3:e101

    Article  PubMed  PubMed Central  Google Scholar 

  23. Lin Y, Zhao Y, Li R et al (2014) PGC-1α is associated with C2C12 Myoblast differentiation. Cent EurJ Biol 9:1030–1036

    CAS  Google Scholar 

  24. Williamson DL, Butler DC, Alway SE (2009) AMPK inhibits myoblast differentiation through a PGC-1α-dependent mechanism. Am J Physiol Endocrinol Metab 297:E304–E314

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr. Cunming Duan from University of Michigan, Ann Arbor, for providing reagents and discussion. We are grateful to Ms. Chunyang Zhang, Indiana University, for reading and commenting on an early version of this manuscript. This work was supported by Natural Scientific Foundation of China (31572261), Natural Science Foundation of Shandong Province, China (ZR2014CM007), and NSFC-Shandong Joint Fund (U1406402).

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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, China

    Xiaoyu Mu, Yunzhang Liu, Jianfeng Zhou, Yun Li, Xiaozhi Rong & Ling Lu

  2. Department of Obstetrics, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, 266003, China

    Weihong Qi

  3. University of Jinan Quancheng College, Jinan, China

    Xiaoyu Mu

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  1. Xiaoyu Mu
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  2. Weihong Qi
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  3. Yunzhang Liu
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  5. Yun Li
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Correspondence to Ling Lu.

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Mu, X., Qi, W., Liu, Y. et al. IGF-II-mediated downregulation of peroxisome proliferator-activated receptor-γ coactivator-1α in myoblast cells involves PI3K/Akt/FoxO1 signaling pathway. Mol Cell Biochem 432, 199–208 (2017). https://doi.org/10.1007/s11010-017-3010-4

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  • DOI: https://doi.org/10.1007/s11010-017-3010-4

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