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BMP11 Negatively Regulates Lipid Metabolism in C2C12 Muscle Cells

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Abstract

Muscle tissue influences energy and protein metabolism throughout the body. Earlier reports demonstrated that bone morphogenetic protein 11 (BMP11) could inhibit skeleton muscle proliferation and development. However, the role of BMP11 in the fatty acid metabolism of muscle has not been explored. In this study, we investigated the physiological functions of exogenous BMP11 on lipid metabolism in C2C12 cells using recombinant BMP11 (rBMP11). Treatment by rBMP11 inhibits myogenesis while inducing lipid accumulation in C2C12 cells. Moreover, induction of rBMP11 inhibits not only fatty acid uptake by downregulation of the fatty acid transport proteins CD36, FATP1, FATP4, and FABP3 but also suppresses fatty acid oxidation by decreasing the levels of p-HSL, ATGL, ACSL, and CGI-58 via Smad 2/3 pathway. Taken together, BMP11 negatively regulates lipid metabolism in muscle cells, which is an opposite result to that in adipocytes where BMP11 improves metabolic homeostasis. Considering the contrasting roles of BMP11 in adipocytes and muscle cells, BMP11 could be a promising target for pharmacological intervention in the treatment of metabolic diseases.

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Abbreviations

Abhd5 :

gene encoding CGI-58

Acvrl1 :

gene encoding activin receptor-like kinase 1 (ALK1)

Acvr1 :

gene encoding activin receptor-like kinase-2 (ALK2)

Acvr1b :

gene encoding activin receptor type-1B (ALK4)

Acvr2a :

gene encoding activin receptor type-2A (ACTRIIA)

Acvr2b :

gene encoding activin receptor type-2B (ACTRIIB)

ACOX1 :

acyl-coenzyme A oxidase 1

ACSL :

long-chainfatty-acid-CoA ligase

ATGL :

adipose triglyceride lipase

BMP :

bone morphogenetic protein

Bmpr1a :

gene encoding bone morphogenetic protein receptor type-1A (ALK3)

Bmpr1b :

gene encoding bone morphogenetic protein receptor type-1B (ALK6)

Bmpr2 :

gene encoding bone morphogenetic protein receptor type 2 (BMPRII)

CD36 :

cluster of differentiation 36

CGI-58 :

comparative gene identification-58

CPT1 :

carnitine palmitoyltransferase 1

FFA :

free fatty acid

FAS :

fatty acid synthase

FATP4 :

long-chain fatty acid transport protein 4

GDF11 :

growth differentiation factor-11

MYH/Myh :

myosin heavy chain/encoding gene

MYOG/Myog :

myogenin/encoding gene

p-HSL :

phosphorylated hormone-sensitive lipase

Plin :

gene encoding perilipin

Slc27a :

gene encoding FATP

Tbx1 :

gene encoding T-box protein 1

Tgfbr-1 :

transforming growth factor beta receptor type 1 (ALK5)

TG :

triglyceride

UCP/Ucp :

uncoupling protein/encoding gene.

References

  1. Morales, P. E., J. L. Bucarey, and A. Espinosa (2017) Muscle lipid metabolism: role of lipid droplets and perilipins. J. Diabetes Res. 2017: 1789395.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Cahova, M., H. Vavrinkova, and L. Kazdova (2007) Glucosefatty acid interaction in skeletal muscle and adipose tissue in insulin resistance. Physiol. Res. 56: 1–15.

    Article  CAS  PubMed  Google Scholar 

  3. Schenk, S. and J. F. Horowitz (2007) Acute exercise increases triglyceride synthesis in skeletal muscle and prevents fatty acid-induced insulin resistance. J. Clin. Invest. 117: 1690–1698.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Watt, M. J. and A. J. Hoy (2012) Lipid metabolism in skeletal muscle: generation of adaptive and maladaptive intracellular signals for cellular function. Am. J. Physiol. Endocrinol. Metab. 302: E1315–E1328.

    Article  CAS  PubMed  Google Scholar 

  5. Amati, F., J. J. Dubé, E. Alvarez-Carnero, M. M. Edreira, P. Chomentowski, P. M. Coen, G. E. Switzer, P. E. Bickel, M. Stefanovic-Racic, F. G. S. Toledo, and B. H. Goodpaster (2011) Skeletal muscle triglycerides, diacylglycerols, and ceramides in insulin resistance: another paradox in endurance-trained athletes? Diabetes. 60: 2588–2597.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Li, L. J., J. Ma, S. B. Li, X. F. Chen, and J. Zhang (2019) Electric pulse stimulation inhibited lipid accumulation on C2C12 myotubes incubated with oleic acid and palmitic acid. Arch. Physiol. Biochem.https://doi.org/10.1080/13813455.2019.1639763.

  7. Guitart, M., O. Osorio-Conles, T. Pentinat, J. Cebrià, J. García-Villoria, D. Sala, D. Sebastián, A. Zorzano, A. Ribes, J. C. Jiménez-Chillarón, C. García-Martínez, and A. M. Gómez-Foix (2014) Fatty acid transport protein 1 (FATP1) localizes in mitochondria in mouse skeletal muscle and regulates lipid and ketone body disposal. PLoS One. 9: e98109.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Kawaguchi, M., Y. Tamura, S. Kakehi, K. Takeno, Y. Sakurai, T. Watanabe, T. Funayama, F. Sato, S. Ikeda, Y. Ogura, N. Saga, H. Naito, Y. Fujitani, A. Kanazawa, R. Kawamori, and H. Watada (2014) Association between expression of FABPpm in skeletal muscle and insulin sensitivity in intramyocellular lipid-accumulated nonobese men. J. Clin. Endocrinol. Metab. 99: 3343–3352.

    Article  CAS  PubMed  Google Scholar 

  9. Bruce, C. R., A. J. Hoy, N. Turner, M. J. Watt, T. L. Allen, K. Carpenter, G. J. Cooney, M. A. Febbraio, and E. W. Kraegen (2009) Overexpression of carnitine palmitoyltransferase-1 in skeletal muscle is sufficient to enhance fatty acid oxidation and improve high-fat diet-induced insulin resistance. Diabetes. 58: 550–558.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Shi, Y. and P. Burn (2004) Lipid metabolic enzymes: emerging drug targets for the treatment of obesity. Nat. Rev. Drug Discov. 3: 695–710.

    Article  CAS  PubMed  Google Scholar 

  11. Luquet, S., J. Lopez-Soriano, D. Holst, C. Gaudel, C. Jehl-Pietri, A. Fredenrich, and P. A. Grimaldi (2004) Roles of peroxisome proliferator-activated receptor delta (PPARdelta) in the control of fatty acid catabolism. A new target for the treatment of metabolic syndrome. Biochimie. 86: 833–837.

    Article  CAS  PubMed  Google Scholar 

  12. Chen, D., M. Zhao, and G. R. Mundy (2004) Bone morphogenetic proteins. Growth Factors. 22: 233–241.

    Article  CAS  PubMed  Google Scholar 

  13. Wozney, J. M., V. Rosen, A. J. Celeste, L. M. Mitsock, M. J. Whitters, R. W. Kriz, R. M. Hewick, and E. A. Wang (1988) Novel regulators of bone formation: molecular clones and activities. Science. 242: 1528–1534.

    Article  CAS  PubMed  Google Scholar 

  14. Urist, M. R. (1965) Bone: formation by autoinduction. Science. 150: 893–899.

    Article  CAS  PubMed  Google Scholar 

  15. Cobourne, M. T. and P. T. Sharpe (2003) Tooth and jaw: molecular mechanisms of patterning in the first branchial arch. Arch. Oral Biol. 48: 1–14.

    Article  CAS  PubMed  Google Scholar 

  16. Walker, R. G., T. Poggioli, L. Katsimpardi, S. M. Buchanan, J. Oh, S. Wattrus, B. Heidecker, Y. W. Fong, L. L. Rubin, P. Ganz, T. B. Thompson, A. J. Wagers, and R. T. Lee (2016) Biochemistry and biology of GDF11 and myostatin: similarities, differences, and questions for future investigation. Circ. Res. 118: 1125–1142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhang, Y., Y. Wei, D. Liu, F. Liu, X. Li, L. Pan, Y. Pang, and D. Chen (2017) Role of growth differentiation factor 11 in development, physiology and disease. Oncotarget. 8: 81604–81616.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Liu, Y., L. Shao, K. Chen, Z. Wang, J. Wang, W. Jing, and M. Hu (2018) GDF11 restrains tumor growth by promoting apoptosis in pancreatic cancer. Onco Targets Ther. 11: 8371–8379.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bajikar, S. S., C. C. Wang, M. A. Borten, E. J. Pereira, K. A. Atkins, and K. A. Janes (2017) Tumor-Suppressor Inactivation of GDF11 occurs by precursor sequestration in triple-negative breast cancer. Dev. Cell. 43: 418–435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Loffredo, F. S., M. L. Steinhauser, S. M. Jay, J. Gannon, J. R. Pancoast, P. Yalamanchi, M. Sinha, C. Dall’Osso, D. Khong, J. L. Shadrach, C. M. Miller, B. S. Singer, A. Stewart, N. Psychogios, R. E. Gerszten, A. J. Hartigan, M. J. Kim, T. Serwold, A. J. Wagers, and R. T. Lee (2013) Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell. 153: 828–839.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Añón-Hidalgo, J., V. Catalán, A. Rodríguez, B. Ramírez, C. Silva, J. C. Galofré, J. Salvador, G. Frühbeck, and J. Gómez-Ambrosi (2019) Circulating GDF11 levels are decreased with age but are unchanged with obesity and type 2 diabetes. Aging (Albany NY). 11: 1733–1744.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Harmon, E. B., A. A. Apelqvist, N. G. Smart, X. Gu, D. H. Osborne, and S. K. Kim (2004) GDF11 modulates NGN3+ islet progenitor cell number and promotes beta-cell differentiation in pancreas development. Development. 131: 6163–6174.

    Article  CAS  PubMed  Google Scholar 

  23. Freitas-Rodríguez, S., F. Rodríguez, and A. R. Folgueras (2016) GDF11 administration does not extend lifespan in a mouse model of premature aging. Oncotarget. 7: 55951–55956.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Kim, T. N., M. S. Park, S. J. Yang, H. J. Yoo, H. J. Kang, W. Song, J. A. Seo, S. G. Kim, N. H. Kim, S. H. Baik, D. S. Choi, and K. M. Choi (2010) Prevalence and determinant factors of sarcopenia in patients with type 2 diabetes: the Korean Sarcopenic Obesity Study (KSOS). Diabetes Care. 33: 1497–1499.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Krssak, M., K. F. Petersen, A. Dresner, L. DiPietro, S. M. Vogel, D. L. Rothman, M. Roden and G. I. Shulman (1999) Intra-myocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia. 42: 113–116.

    Article  CAS  PubMed  Google Scholar 

  26. Lu, B., J. Zhong, J. Pan, X. Yuan, M. Ren, L. Jiang, Y. Yang, G. Zhang, D. Liu, C. Zhang (2019) Gdf11 gene transfer prevents high fat diet-induced obesity and improves metabolic homeostasis in obese and STZ-induced diabetic mice. J Transl Med. 17: 422.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Luo, H., Y. Guo, Y. Liu, Y. Wang, R. Zheng, Y. Ban, L. Peng, Q. Yuan, and W. Liu (2019) Growth differentiation factor 11 inhibits adipogenic differentiation by activating TGF-beta/Smad signalling pathway. Cell Prolif. 52: e12631.

    PubMed  PubMed Central  Google Scholar 

  28. Lukaszuk, B., I. Bialuk, J. Górski, M. Zajączkiewicz, M. M. Winnicka, and A. Chabowski (2012) A single bout of exercise increases the expression of glucose but not fatty acid transporters in skeletal muscle of IL-6 KO mice. Lipids. 47: 763–772.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Pedersen, B. K. and M. A. Febbraio (2012) Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat. Rev. Endocrinol. 8: 457–465.

    Article  CAS  PubMed  Google Scholar 

  30. Mukherjee, S., K. R. Aseer, and J. W. Yun (2020) Roles of macrophage colony stimulating factor in white and brown adipocytes. Biotechnol. Bioprocess Eng. 25: 29–38.

    Article  CAS  Google Scholar 

  31. Jackson, V. M., D. M. Breen, J. P. Fortin, A. Liou, J. B. Kuzmiski, A. K. Loomis, M. L. Rives, B. Shah, and P. A. Carpino (2015) Latest approaches for the treatment of obesity. Expert. Opin. Drug Discov. 10: 825–839.

    Article  CAS  PubMed  Google Scholar 

  32. Jang, M. H., N. H. Kang, S. Mukherjee, and J. W. Yun (2018) Theobromine, a methylxanthine in cocoa bean, stimulates thermogenesis by inducing white fat browning and activating brown adipocytes. Biotechnol. Bioprocess Eng. 23: 617–626.

    Article  CAS  Google Scholar 

  33. Manigandan, S. and J. W. Yun (2020) Urolithin A induces brown-like phenotype in 3T3-L1 white adipocytes via β3-adrenergic receptor-p38 MAPK signaling pathway. Biotechnol. Bioprocess Eng. 25: 345–355.

    Article  CAS  Google Scholar 

  34. Egerman, M. A., S. M. Cadena, J. A. Gilbert, A. Meyer, H. N. Nelson, S. E. Swalley, C. Mallozzi, C. Jacobi, L. L. Jennings, I. Clay, G. Laurent, S. Ma, S. Brachat, E. Lach-Trifilieff, T. Shavlakadze, A. U. Trendelenburg, A. S. Brack, and D. J. Glass (2015) GDF11 increases with age and inhibits skeletal muscle regeneration. Cell Metab. 22: 164–174.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Jeanplong, F., S. J. Falconer, M. Thomas, K. G. Matthews, J. M. Oldham, T. Watson, and C. D. McMahon (2012) Growth and differentiation factor-11 is developmentally regulated in skeletal muscle and inhibits myoblast differentiation. Open J. Mol. Integr. Physiol. 2:127–138.

    Article  CAS  Google Scholar 

  36. Fujita, T., S. Furukawa, K. Morita, T. Ishihara, M. Shiotani, Y. Matsushita, M. Matsuda, and I. Shimomura (2005) Glucosamine induces lipid accumulation and adipogenic change in C2C12 myoblasts. Biochem. Biophys. Res. Commun. 328: 369–374.

    Article  CAS  PubMed  Google Scholar 

  37. Yin, C., Q. Long, T. Lei, X. Chen, H. Long, B. Feng, Y. Peng, Y. Wu, and Z. Yang (2009) Lipid accumulation mediated by adiponectin in C2C12 myogenesis. BMB Rep. 42: 667–672.

    Article  CAS  PubMed  Google Scholar 

  38. McCormack, S. E., M. A. McCarthy, S. G. Harrington, L. Farilla, M. I. Hrovat, D. M. Systrom, B. J. Thomas, M. Torriani, K. McInnis, S. K. Grinspoon, and A. Fleischman (2014) Effects of exercise and lifestyle modification on fitness, insulin resistance, skeletal muscle oxidative phosphorylation and intramyocellular lipid content in obese children and adolescents. Pediatric Obesity. 9: 281–291

    Article  CAS  PubMed  Google Scholar 

  39. Watt, M. J., G. J. F. Heigenhauser, D. J. Dyck, and L. L. Spriet (2002) Intramuscular triacylglycerol, glycogen and acetyl group metabolism during 4 h of moderate exercise in man. J. Physiol. 541: 969–978.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Pan, D. A., S. Lillioj, A. D. Kriketos, M. R. Milner, L. A. Baur, C. Bogardus, A. B. Jenkins, and L. H. Storlien (1997) Skeletal muscle triglyceride levels are inversely related to insulin action. Diabetes. 46: 983–988.

    Article  CAS  PubMed  Google Scholar 

  41. Goodpaster, B. H., R. Teriault, S. C. Watkins, and D. E. Kelley (2000) Intramuscular lipid content is increased in obesity and decreased by weight loss. Metabolism. 49: 467–472.

    Article  CAS  PubMed  Google Scholar 

  42. Cortright, R. N., D. M. Muoio, and G. L. Dohm (1997) Skeletal muscle lipid metabolism: A frontier for new insights into fuel homeostasis. J. Nutr. Biochem. 8: 228–245.

    Article  CAS  Google Scholar 

  43. Newsom, S. A., S. Schenk, M. Li, A. C. Everett, and J. F. Horowitz (2011) High fatty acid availability after exercise alters the regulation of muscle lipid metabolism. Metabolism. 60: 852–859.

    Article  CAS  PubMed  Google Scholar 

  44. Van Hall, G. (2015) The physiological regulation of skeletal muscle fatty acid supply and oxidation during moderate-intensity exercise. Sports Med. 45: 23–32.

    Article  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by a National Research Foundation of Korea grant funded by the Korean government (MSIT) (No. 2019R1A2C2002163).

The authors declare no conflict of interest.

Neither ethical approval nor informed consent was required for this study.

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Authors and Affiliations

  1. Department of Biotechnology, Daegu University, Gyeongsan, 38453, Korea

    Huong Giang Pham & Jong Won Yun

  2. Department of Food Science and Technology, Chung-Ang University, Anseong, 17546, Korea

    Jong Pil Park

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Pham, H.G., Park, J.P. & Yun, J.W. BMP11 Negatively Regulates Lipid Metabolism in C2C12 Muscle Cells. Biotechnol Bioproc E 25, 670–680 (2020). https://doi.org/10.1007/s12257-020-0254-8

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