Skip to main content

Advertisement

SpringerLink
Log in

Genes interconnecting AMPK and TREM-1 and associated microRNAs in rotator cuff tendon injury

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Fatty infiltration and inflammation delay the healing responses and raise major concerns in the therapeutic management of rotator cuff tendon injuries (RCTI). Our evaluations showed the upregulation of ‘metabolic check point’ AMPK and inflammatory molecule, TREM-1 from shoulder biceps tendons collected from RCTI subjects. However, the epigenetic regulation of these biomolecules by miRNAs is largely unknown and it is likely that a deeper understanding of the mechanism of action can have therapeutic potential for RCTI. Based on this background, we have evaluated the miRNAs from RCTI patients with fatty infiltration and inflammation (FI group) and compared with RCTI patients without fatty infiltration and inflammation (No-FI group). NetworkAnalyst was employed to evaluate the genes interconnecting AMPK and TREM-1 pathway, using PRKAA1 (AMPK), TREM-1, HIF1α, HMGB1, and AGER as input genes. The most relevant miRNAs were screened by considering the fold change below − 7.5 and the number of target genes 10 and more which showed 13 miRNAs and 216 target genes. The exact role of these miRNAs in the fatty infiltration and inflammation associated with RCTI is still unknown and the understanding of biological activity of these miRNAs can pave ways to develop miRNA-based therapeutics in the management of RCTI.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Luan T, Liu X, Easley JT et al (2015) Muscle atrophy and fatty infiltration after an acute rotator cuff repair in a sheep model. Muscles Ligaments Tendons J 5:106–112

    Article  PubMed  PubMed Central  Google Scholar 

  2. Oak NR, Gumucio JP, Flood MD et al (2014) Inhibition of 5-LOX, COX-1, and COX-2 increases tendon healing and reduces muscle fibrosis and lipid accumulation after rotator cuff repair. Am J Sports Med 42:2860–2868. https://doi.org/10.1177/0363546514549943

    Article  PubMed  PubMed Central  Google Scholar 

  3. Laron D, Samagh SP, Liu X et al (2012) Muscle degeneration in rotator cuff tears. J Shoulder Elbow Surg 21:164–174. https://doi.org/10.1016/j.jse.2011.09.027

    Article  PubMed  Google Scholar 

  4. Thankam FG, Dilisio MF, Agrawal DK (2016) Immunobiological factors aggravating the fatty infiltration on tendons and muscles in rotator cuff lesions. Mol Cell Biochem 417:17–33. https://doi.org/10.1007/s11010-016-2710-5

    Article  CAS  PubMed  Google Scholar 

  5. Goutallier D, Postel J-M, Gleyze P et al (2003) Influence of cuff muscle fatty degeneration on anatomic and functional outcomes after simple suture of full-thickness tears. J Shoulder Elb Surg Am Shoulder Elb Surg Al 12:550–554. https://doi.org/10.1016/S1058274603002118

    Article  Google Scholar 

  6. Thankam FG, Dilisio MF, Agrawal DK (2016) Immunobiological factors aggravating the fatty infiltration on tendons and muscles in rotator cuff lesions. Mol Cell Biochem doi. https://doi.org/10.1007/s11010-016-2710-5

    Article  Google Scholar 

  7. Thankam FG, Dilisio MF, Dietz NE, Agrawal DK (2016) TREM-1, HMGB1 and RAGE in the shoulder tendon: dual mechanisms for inflammation based on the coincidence of glenohumeral arthritis. PLOS ONE 11:e0165492. https://doi.org/10.1371/journal.pone.0165492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Rees JD (2006) Current concepts in the management of tendon disorders. Rheumatology 45:508–521. https://doi.org/10.1093/rheumatology/kel046

    Article  CAS  PubMed  Google Scholar 

  9. Joshi SK, Liu X, Samagh SP et al (2013) mTOR regulates fatty infiltration through SREBP-1 and PPARγ after a combined massive rotator cuff tear and suprascapular nerve injury in rats. J Orthop Res Off Publ Orthop Res Soc 31:724–730. https://doi.org/10.1002/jor.22254

    Article  CAS  Google Scholar 

  10. Jiang LQ, De Castro Barbosa T, Massart J et al (2015) Diacylglycerol kinase δ regulates AMPK signaling, lipid metabolism and skeletal muscle energetics. Am J Physiol—Endocrinol Metab. https://doi.org/10.1152/ajpendo.00209.2015 00209.2015.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Hardie DG (2011) AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev 25:1895–1908. https://doi.org/10.1101/gad.17420111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hardie DG (2008) AMPK: a key regulator of energy balance in the single cell and the whole organism. Int J Obes 32:S7–S12. https://doi.org/10.1038/ijo.2008.116

    Article  CAS  Google Scholar 

  13. Godlewski J, Nowicki MO, Bronisz A et al (2010) MicroRNA-451 regulates LKB1/AMPK signaling and allows adaptation to metabolic stress in glioma cells. Mol Cell 37:620–632. https://doi.org/10.1016/j.molcel.2010.02.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Chen H, Untiveros GM, McKee LAK et al (2012) Micro-RNA-195 and -451 regulate the LKB1/AMPK signaling axis by targeting MO25. PLoS ONE 7:e41574. https://doi.org/10.1371/journal.pone.0041574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Thankam FG, Boosani CS, Dilisio MF et al (2016) MicroRNAs associated with shoulder tendon matrisome disorganization in glenohumeral arthritis. PLOS ONE 11:e0168077. https://doi.org/10.1371/journal.pone.0168077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Xia J, Gill EE, Hancock REW (2015) NetworkAnalyst for statistical, visual and network-based meta-analysis of gene expression data. Nat Protoc 10:823–844. https://doi.org/10.1038/nprot.2015.052

    Article  CAS  PubMed  Google Scholar 

  17. Xia J, Benner MJ, Hancock REW (2014) NetworkAnalyst—integrative approaches for protein-protein interaction network analysis and visual exploration. Nucleic Acids Res 42:W167–W174. https://doi.org/10.1093/nar/gku443

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chaudhury S, Dines JS, Delos D et al (2012) Role of fatty infiltration in the pathophysiology and outcomes of rotator cuff tears. Arthritis Care Res 64:76–82. https://doi.org/10.1002/acr.20552

    Article  Google Scholar 

  19. Matsumoto F, Uhthoff HK, Trudel G, Loehr JF (2002) Delayed tendon reattachment does not reverse atrophy and fat accumulation of the supraspinatus—an experimental study in rabbits. J Orthop Res 20:357–363. https://doi.org/10.1016/S0736-0266(01)00093-6

    Article  PubMed  Google Scholar 

  20. Steinbacher P, Tauber M, Kogler S et al (2010) Effects of rotator cuff ruptures on the cellular and intracellular composition of the human supraspinatus muscle. Tissue Cell 42:37–41. https://doi.org/10.1016/j.tice.2009.07.001

    Article  CAS  PubMed  Google Scholar 

  21. O’Connell RM, Rao DS, Chaudhuri AA, Baltimore D (2010) Physiological and pathological roles for microRNAs in the immune system. Nat Rev Immunol 10:111–122. https://doi.org/10.1038/nri2708

    Article  CAS  PubMed  Google Scholar 

  22. Dangwal S, Thum T (2013) MicroRNAs in platelet physiology and pathology. Hämostaseologie 33:17–20. https://doi.org/10.5482/HAMO-13-01-0002

    Article  CAS  PubMed  Google Scholar 

  23. Tüfekci KU, Öner MG, Meuwissen RLJ, Genç Ş (2014) The role of microRNAs in human diseases. In: Yousef M, Allmer J (eds) miRNomics: microRNA biology and computational analysis. Humana Press, Totowa, pp 33–50

    Chapter  Google Scholar 

  24. Yuan M, Zhang L, You F et al (2017) MiR-145-5p regulates hypoxia-induced inflammatory response and apoptosis in cardiomyocytes by targeting CD40. Mol Cell Biochem. https://doi.org/10.1007/s11010-017-2982-4

    Article  PubMed  Google Scholar 

  25. Cui S-Y, Wang R, Chen L-B (2014) MicroRNA-145: a potent tumour suppressor that regulates multiple cellular pathways. J Cell Mol Med 18:1913–1926. https://doi.org/10.1111/jcmm.12358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Raisch J (2013) Role of microRNAs in the immune system, inflammation and cancer. World J Gastroenterol 19:2985. https://doi.org/10.3748/wjg.v19.i20.2985

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Li Y, Shi X (2013) MicroRNAs in the regulation of TLR and RIG-I pathways. Cell Mol Immunol 10:65–71. https://doi.org/10.1038/cmi.2012.55

    Article  CAS  PubMed  Google Scholar 

  28. Torres A, Torres K, Pesci A et al (2012) Deregulation of miR-100, miR-99a and miR-199b in tissues and plasma coexists with increased expression of mTOR kinase in endometrioid endometrial carcinoma. BMC Cancer 12:. https://doi.org/10.1186/1471-2407-12-369

  29. Jing L, Hou Y, Wu H et al (2015) Transcriptome analysis of mRNA and miRNA in skeletal muscle indicates an important network for differential Residual Feed Intake in pigs. Sci Rep 5:11953. https://doi.org/10.1038/srep11953

    Article  PubMed  PubMed Central  Google Scholar 

  30. Margolis LM, Rivas DA, Berrone M et al (2016) Prolonged calorie restriction downregulates skeletal muscle mTORC1 signaling independent of dietary protein intake and associated microRNA Expression. Front Physiol. https://doi.org/10.3389/fphys.2016.00445

    Article  PubMed  PubMed Central  Google Scholar 

  31. Palagani A, Op de Beeck K, Naulaerts S et al (2014) Ectopic microRNA-150-5p transcription sensitizes glucocorticoid therapy response in MM1S multiple myeloma cells but fails to overcome hormone therapy resistance in MM1R cells. PLoS ONE 9:e113842. https://doi.org/10.1371/journal.pone.0113842

    Article  PubMed  PubMed Central  Google Scholar 

  32. Punga T, Le Panse R, Andersson M et al (2014) Circulating miRNAs in myasthenia gravis: miR-150-5p as a new potential biomarker. Ann Clin Transl Neurol 1:49–58. https://doi.org/10.1002/acn3.24

    Article  CAS  PubMed  Google Scholar 

  33. Van der Goten J, Vanhove W, Lemaire K et al (2014) Integrated miRNA and mRNA expression profiling in inflamed colon of patients with ulcerative colitis. PLoS ONE 9:e116117. https://doi.org/10.1371/journal.pone.0116117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Brogaard L, Heegaard PMH, Larsen LE et al (2016) Late regulation of immune genes and microRNAs in circulating leukocytes in a pig model of influenza A (H1N2) infection. Sci Rep 6:. https://doi.org/10.1038/srep21812

  35. Lee C-H, Kuo W-H, Lin C-C et al (2013) MicroRNA-regulated protein–protein interaction networks and their functions in breast cancer. Int J Mol Sci 14:11560–11606. https://doi.org/10.3390/ijms140611560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhou H, Rigoutsos I (2014) MiR-103a-3p targets the 5′ UTR of GPRC5A in pancreatic cells. RNA 20:1431–1439. https://doi.org/10.1261/rna.045757.114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bork-Jensen J, Thuesen A, Bang-Bertelsen C et al (2014) Genetic versus non-genetic regulation of miR-103, miR-143 and miR-483-3p expression in adipose tissue and their metabolic implications—a twin study. Genes 5:508–517. https://doi.org/10.3390/genes5030508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. McGregor A, Choi RS M (2011) microRNAs in the regulation of adipogenesis and obesity. Curr Mol Med 11:304–316. https://doi.org/10.2174/156652411795677990

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wu J, Ji A, Wang X et al (2015) MicroRNA-195-5p, a new regulator of Fra-1, suppresses the migration and invasion of prostate cancer cells. J Transl Med 13:. https://doi.org/10.1186/s12967-015-0650-6

  40. Cai C, Chen Q-B, Han Z-D et al (2015) miR-195 inhibits tumor progression by targeting RPS6KB1 in human prostate cancer. Clin Cancer Res 21:4922–4934. https://doi.org/10.1158/1078-0432.CCR-15-0217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ding J, Huang S, Wang Y et al (2013) Genome-wide screening reveals that miR-195 targets the TNF-α/NF-κB pathway by down-regulating IκB kinase alpha and TAB3 in hepatocellular carcinoma. Hepatology 58:654–666. https://doi.org/10.1002/hep.26378

    Article  CAS  PubMed  Google Scholar 

  42. Smolle E, Haybaeck J (2014) Non-coding RNAs and lipid metabolism. Int J Mol Sci 15:13494–13513. https://doi.org/10.3390/ijms150813494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Fei X, Qi M, Wu B et al (2012) MicroRNA-195-5p suppresses glucose uptake and proliferation of human bladder cancer T24 cells by regulating GLUT3 expression. FEBS Lett 586:392–397. https://doi.org/10.1016/j.febslet.2012.01.006

    Article  CAS  PubMed  Google Scholar 

  44. Yang W-M, Jeong H-J, Park S-Y, Lee W (2014) Saturated fatty acid-induced miR-195 impairs insulin signaling and glycogen metabolism in HepG2 cells. FEBS Lett 588:3939–3946. https://doi.org/10.1016/j.febslet.2014.09.006

    Article  CAS  PubMed  Google Scholar 

  45. Zhang Q, Xu M, Qu Y et al (2015) Analysis of the differential expression of circulating microRNAs during the progression of hepatic fibrosis in patients with chronic hepatitis B virus infection. Mol Med Rep. https://doi.org/10.3892/mmr.2015.4221

    Article  PubMed  PubMed Central  Google Scholar 

  46. Jafarzadeh M, Soltani BM, Dokanehiifard S et al (2016) Experimental evidences for hsa-miR-497-5p as a negative regulator of SMAD3 gene expression. Gene 586:216–221. https://doi.org/10.1016/j.gene.2016.04.003

    Article  CAS  PubMed  Google Scholar 

  47. Gheinani AH, Kiss B, Moltzahn F et al (2017) Characterization of miRNA-regulated networks, hubs of signaling, and biomarkers in obstruction-induced bladder dysfunction. JCI Insight 2:. https://doi.org/10.1172/jci.insight.89560

  48. Ye E-A, Liu L, Jiang Y et al (2016) miR-15a/16 reduces retinal leukostasis through decreased pro-inflammatory signaling. J Neuroinflammation 13:. https://doi.org/10.1186/s12974-016-0771-8

  49. Hou N, Han J, Li J et al (2014) MicroRNA profiling in human colon cancer cells during 5-fluorouracil-induced autophagy. PLoS ONE 9:e114779. https://doi.org/10.1371/journal.pone.0114779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Druz A, Chen Y-C, Guha R et al (2013) Large-scale screening identifies a novel microRNA, miR-15a-3p, which induces apoptosis in human cancer cell lines. RNA Biol 10:287–300. https://doi.org/10.4161/rna.23339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chen Z, Qiu H, Ma L et al (2016) miR-30e-5p and miR-15a synergistically regulate fatty acid metabolism in goat mammary epithelial cells via LRP6 and YAP1. Int J Mol Sci 17:1909. https://doi.org/10.3390/ijms17111909

  52. Rinnerthaler G, Hackl H, Gampenrieder S et al (2016) miR-16-5p Is a stably-expressed housekeeping microRNA in breast cancer tissues from primary tumors and from metastatic sites. Int J Mol Sci 17:156. https://doi.org/10.3390/ijms17020156

    Article  CAS  PubMed Central  Google Scholar 

  53. Yu A-M, Pan Y-Z (2012) Noncoding microRNAs: small RNAs play a big role in regulation of ADME? Acta Pharm Sin B 2:93–101. https://doi.org/10.1016/j.apsb.2012.02.011

    Article  CAS  PubMed  Google Scholar 

  54. Zhang J, Song Y, Zhang C et al (2015) Circulating MiR-16-5p and MiR-19b-3p as two novel potential biomarkers to indicate progression of gastric cancer. Theranostics 5:733–745. https://doi.org/10.7150/thno.10305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kishore A, Borucka J, Petrkova J, Petrek M (2014) Novel Insights into miRNA in lung and heart inflammatory diseases. Mediators Inflamm 2014:1–27. https://doi.org/10.1155/2014/259131

    Article  CAS  Google Scholar 

  56. Prajapati P, Sripada L, Singh K et al (2015) TNF-α regulates miRNA targeting mitochondrial complex-I and induces cell death in dopaminergic cells. Biochim Biophys Acta BBA—Mol Basis Dis 1852:451–461. https://doi.org/10.1016/j.bbadis.2014.11.019

    Article  CAS  Google Scholar 

  57. Aranda JF, Madrigal-Matute J, Rotllan N, Fernández-Hernando C (2013) MicroRNA modulation of lipid metabolism and oxidative stress in cardiometabolic diseases. Free Radic Biol Med 64:31–39. https://doi.org/10.1016/j.freeradbiomed.2013.07.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Liu Z, Wang Y, Borlak J, Tong W (2016) Mechanistically linked serum miRNAs distinguish between drug induced and fatty liver disease of different grades. Sci Rep 6:. https://doi.org/10.1038/srep23709

  59. Hatziapostolou M, Polytarchou C, Iliopoulos D (2013) miRNAs link metabolic reprogramming to oncogenesis. Trends Endocrinol Metab 24:361–373. https://doi.org/10.1016/j.tem.2013.03.002

    Article  CAS  PubMed  Google Scholar 

  60. Guo Z, Gong J, Li Y et al (2016) Mucosal microRNAs expression profiles before and after exclusive enteral nutrition therapy in adult patients with Crohn’s disease. Nutrients 8:519. https://doi.org/10.3390/nu8080519

    Article  CAS  PubMed Central  Google Scholar 

  61. Yu H-R, Hsu T-Y, Huang H-C et al (2016) Comparison of the functional microRNA expression in immune cell subsets of neonates and adults. Front Immunol. https://doi.org/10.3389/fimmu.2016.00615

    Article  PubMed  PubMed Central  Google Scholar 

  62. Roessler C, Kuhlmann K, Hellwing C et al (2017) Impact of polyunsaturated fatty acids on miRNA profiles of monocytes/macrophages and endothelial cells—a pilot study. Int J Mol Sci 18:284. https://doi.org/10.3390/ijms18020284

    Article  CAS  PubMed Central  Google Scholar 

  63. Blotta MH, Marshall JD, DeKruyff RH, Umetsu DT (1996) Cross-linking of the CD40 ligand on human CD4+ T lymphocytes generates a costimulatory signal that up-regulates IL-4 synthesis. J Immunol Baltim Md 1950 156:3133–3140

    CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the State of Nebraska LB506 Grant to DKA and Creighton University LB692 Grant to MFD. The research work of DK Agrawal is also supported by R01HL116042, R01HL120659 and R01HL144125 awards from the National Heart, Lung and Blood Institute, National Institutes of Health, USA. The content of this original research article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the State of Nebraska.

Author information

Authors and Affiliations

  1. Departments of Clinical & Translational Science and Orthopedic Surgery, Creighton University School of Medicine, Omaha, NE, 68178, USA

    Finosh G. Thankam, Chandra S. Boosani, Matthew F. Dilisio, R. Michael Gross & Devendra K. Agrawal

  2. Department of Clinical & Translational Science, The Peekie Nash Carpenter Endowed Chair in Medicine, CRISS II Room 510, 2500 California Plaza, Omaha, NE, 68178, USA

    Devendra K. Agrawal

Authors
  1. Finosh G. Thankam
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chandra S. Boosani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Matthew F. Dilisio
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. Michael Gross
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Devendra K. Agrawal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Devendra K. Agrawal.

Ethics declarations

Conflict of interest

The authors have no conflict of interest to disclose.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 69 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Thankam, F.G., Boosani, C.S., Dilisio, M.F. et al. Genes interconnecting AMPK and TREM-1 and associated microRNAs in rotator cuff tendon injury. Mol Cell Biochem 454, 97–109 (2019). https://doi.org/10.1007/s11010-018-3456-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-018-3456-z

Keywords

Search

Navigation