Skip to main content
SpringerLink
Log in

Complete failure of insulin-transmitted signaling, but not obesity-induced insulin resistance, impairs respiratory chain function in muscle

  • Original Article
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

The role of mitochondrial dysfunction in the development of insulin resistance and type 2 diabetes remains controversial. In order to specifically define the relationship between insulin receptor (InsR) signaling, insulin resistance, hyperglycemia, hyperlipidemia and mitochondrial function, we analyzed mitochondrial performance of insulin-sensitive, slow-oxidative muscle in four different mouse models. In obese but normoglycemic ob/ob mice as well as in obese but diabetic mice under high-fat diet, mitochondrial performance remained unchanged even though intramyocellular diacylglycerols (DAGs), triacylglycerols (TAGs), and ceramides accumulated. In contrast, in muscle-specific InsR knockout (MIRKO) and streptozotocin (STZ)-treated hypoinsulinemic, hyperglycemic mice, levels of mitochondrial respiratory chain complexes and mitochondrial function were markedly reduced. In STZ, but not in MIRKO mice, this was caused by reduced transcription of mitochondrial genes mediated via decreased PGC-1α expression. We conclude that mitochondrial dysfunction is not causally involved in the pathogenesis of obesity-associated insulin resistance under normoglycemic conditions. However, obesity-associated type 2 diabetes and accumulation of DAGs or TAGs is not associated with impaired mitochondrial function. In contrast, chronic hypoinsulinemia and hyperglycemia as seen in STZ-treated mice as well as InsR deficiency in muscle of MIRKO mice lead to mitochondrial dysfunction. We postulate that decreased mitochondrial mass and/or performance in skeletal muscle of non-diabetic, obese or type 2 diabetic, obese patients observed in clinical studies must be explained by genetic predisposition, physical inactivity, or other still unknown factors.

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
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Finck BN, Bernal-Mizrachi C, Han DH, Coleman T, Sambandam N, LaRiviere LL, Holloszy JO, Semenkovich CF, Kelly DP (2005) A potential link between muscle peroxisome proliferator-activated receptor-alpha signaling and obesity-related diabetes. Cell Metab 1:133–144

    Article  PubMed  CAS  Google Scholar 

  2. Lowell BB, Shulman GI (2005) Mitochondrial dysfunction and type 2 diabetes. Science 307:384–387

    Article  PubMed  CAS  Google Scholar 

  3. Holland WL, Summers SA (2008) Sphingolipids, insulin resistance, and metabolic disease: new insights from in vivo manipulation of sphingolipid metabolism. Endocr Rev 29:381–402

    Article  PubMed  CAS  Google Scholar 

  4. Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI (2004) Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med 350:664–671

    Article  PubMed  CAS  Google Scholar 

  5. Petersen KF, Dufour S, Shulman GI (2005) Decreased insulin-stimulated ATP synthesis and phosphate transport in muscle of insulin-resistant offspring of type 2 diabetic parents. PLoS Med 2:e233

    Article  PubMed  Google Scholar 

  6. Patti ME, Butte AJ, Crunkhorn S, Cusi K, Berria R, Kashyap S, Miyazaki Y, Kohane I, Costello M, Saccone R et al (2003) Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1. Proc Natl Acad Sci USA 100:8466–8471

    Article  PubMed  CAS  Google Scholar 

  7. Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstrale M, Laurila E et al (2003) PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet 34:267–273

    Article  PubMed  CAS  Google Scholar 

  8. Szendroedi J, Roden M (2009) Ectopic lipids and organ function. Curr Opin Lipidol 20:50–56

    Article  PubMed  CAS  Google Scholar 

  9. Schrauwen P, Schrauwen-Hinderling V, Hoeks J, Hesselink MK (2009) Mitochondrial dysfunction and lipotoxicity. Biochim Biophys Acta 1801:266–271

    PubMed  Google Scholar 

  10. Wredenberg A, Freyer C, Sandstrom ME, Katz A, Wibom R, Westerblad H, Larsson NG (2006) Respiratory chain dysfunction in skeletal muscle does not cause insulin resistance. Biochem Biophys Res Commun 350:202–207

    Article  PubMed  CAS  Google Scholar 

  11. Pospisilik JA, Knauf C, Joza N, Benit P, Orthofer M, Cani PD, Ebersberger I, Nakashima T, Sarao R, Neely G et al (2007) Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes. Cell 131:476–491

    Article  PubMed  CAS  Google Scholar 

  12. Han DH, Hancock CR, Jung SR, Higashida K, Kim SH, Holloszy JO (2011) Deficiency of the mitochondrial electron transport chain in muscle does not cause insulin resistance. PLoS One 6:e19739

    Article  PubMed  CAS  Google Scholar 

  13. Schiff M, Loublier S, Coulibaly A, Benit P, de Ogier B, Rustin P (2009) Mitochondria and diabetes mellitus: untangling a conflictive relationship? J Inherit Metab Dis 32:684–698

    Article  PubMed  CAS  Google Scholar 

  14. Bruning JC, Michael MD, Winnay JN, Hayashi T, Horsch D, Accili D, Goodyear LJ, Kahn CR (1998) A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. Mol Cell 2:559–569

    Article  PubMed  CAS  Google Scholar 

  15. Wade JM, Juneja P, MacKay AW, Graham J, Havel PJ, Tecott LH, Goulding EH (2008) Synergistic impairment of glucose homeostasis in ob/ob mice lacking functional serotonin 2C receptors. Endocrinology 149:955–961

    Article  PubMed  CAS  Google Scholar 

  16. Kuznetsov AV, Veksler V, Gellerich FN, Saks V, Margreiter R, Kunz WS (2008) Analysis of mitochondrial function in situ in permeabilized muscle fibers, tissues and cells. Nat Protoc 3:965–976

    Article  PubMed  CAS  Google Scholar 

  17. Franko A, Mayer S, Thiel G, Mercy L, Arnould T, Hornig-Do HT, Wiesner RJ, Goffart S (2008) CREB-1alpha is recruited to and mediates upregulation of the cytochrome c promoter during enhanced mitochondrial biogenesis accompanying skeletal muscle differentiation. Mol Cell Biol 28:2446–2459

    Article  PubMed  CAS  Google Scholar 

  18. Kleist-Retzow JC, Hornig-Do HT, Schauen M, Eckertz S, Dinh TA, Stassen F, Lottmann N, Bust M, Galunska B, Wielckens K et al (2007) Impaired mitochondrial Ca2+ homeostasis in respiratory chain-deficient cells but efficient compensation of energetic disadvantage by enhanced anaerobic glycolysis due to low ATP steady state levels. Exp Cell Res 313:3076–3089

    Article  Google Scholar 

  19. Kerner J, Parland WK, Minkler PE, Hoppel CL (2008) Rat liver mitochondrial carnitine palmitoyltransferase-I, hepatic carnitine, and malonyl-CoA: effect of starvation. Arch Physiol Biochem 114:161–170

    Article  PubMed  CAS  Google Scholar 

  20. Rustin P, Chretien D, Bourgeron T, Gerard B, Rotig A, Saudubray JM, Munnich A (1994) Biochemical and molecular investigations in respiratory chain deficiencies. Clin Chim Acta 228:35–51

    Article  PubMed  CAS  Google Scholar 

  21. Hornig-Do HT, von Kleist-Retzow JC, Lanz K, Wickenhauser C, Kudin AP, Kunz WS, Wiesner RJ, Schauen M (2007) Human epidermal keratinocytes accumulate superoxide due to low activity of Mn-SOD, leading to mitochondrial functional impairment. J Invest Dermatol 127:1084–1093

    Article  PubMed  CAS  Google Scholar 

  22. Huang TT, Naeemuddin M, Elchuri S, Yamaguchi M, Kozy HM, Carlson EJ, Epstein CJ (2006) Genetic modifiers of the phenotype of mice deficient in mitochondrial superoxide dismutase. Hum Mol Genet 15:1187–1194

    Article  PubMed  CAS  Google Scholar 

  23. Belgardt BF, Mauer J, Wunderlich FT, Ernst MB, Pal M, Spohn G, Bronneke HS, Brodesser S, Hampel B, Schauss AC et al (2010) Hypothalamic and pituitary c-Jun N-terminal kinase 1 signaling coordinately regulates glucose metabolism. Proc Natl Acad Sci USA 107:6028–6033

    Article  PubMed  CAS  Google Scholar 

  24. Shaner RL, Allegood JC, Park H, Wang E, Kelly S, Haynes CA, Sullards MC, Merrill AH Jr (2009) Quantitative analysis of sphingolipids for lipidomics using triple quadrupole and quadrupole linear ion trap mass spectrometers. J Lipid Res 50:1692–1707

    Article  PubMed  CAS  Google Scholar 

  25. O’Brien PC (1984) Procedures for comparing samples with multiple endpoints. Biometrics 40:1079–1087

    Article  PubMed  Google Scholar 

  26. Lindstrom P (2007) The physiology of obese-hyperglycemic mice [ob/ob mice]. Sci World J 7:666–685

    Article  Google Scholar 

  27. Freeman HC, Hugill A, Dear NT, Ashcroft FM, Cox RD (2006) Deletion of nicotinamide nucleotide transhydrogenase: a new quantitative trait locus accounting for glucose intolerance in C57BL/6J mice. Diabetes 55:2153–2156

    Article  PubMed  CAS  Google Scholar 

  28. Turpin SM, Ryall JG, Southgate R, Darby I, Hevener AL, Febbraio MA, Kemp BE, Lynch GS, Watt MJ (2009) Examination of ‘lipotoxicity’ in skeletal muscle of high-fat fed and ob/ob mice. J Physiol 587:1593–1605

    Article  PubMed  CAS  Google Scholar 

  29. Schagger H, Pfeiffer K (2000) Supercomplexes in the respiratory chains of yeast and mammalian mitochondria. EMBO J 19:1777–1783

    Article  PubMed  CAS  Google Scholar 

  30. Acin-Perez R, Fernandez-Silva P, Peleato ML, Perez-Martos A, Enriquez JA (2008) Respiratory active mitochondrial supercomplexes. Mol Cell 32:529–539

    Article  PubMed  CAS  Google Scholar 

  31. Bonnard C, Durand A, Peyrol S, Chanseaume E, Chauvin MA, Morio B, Vidal H, Rieusset J (2008) Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice. J Clin Invest 118:789–800

    PubMed  CAS  Google Scholar 

  32. Cheng Z, Guo S, Copps K, Dong X, Kollipara R, Rodgers JT, Depinho RA, Puigserver P, White MF (2009) Foxo1 integrates insulin signaling with mitochondrial function in the liver. Nat Med 15:1307–1311

    Article  PubMed  CAS  Google Scholar 

  33. Canto C, Auwerx J (2009) PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr Opin Lipidol 20:98–105

    Article  PubMed  CAS  Google Scholar 

  34. Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132:27–42

    Article  PubMed  CAS  Google Scholar 

  35. Kim I, Rodriguez-Enriquez S, Lemasters JJ (2007) Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys 462:245–253

    Article  PubMed  CAS  Google Scholar 

  36. Tanida I, Ueno T, Kominami E (2004) LC3 conjugation system in mammalian autophagy. Int J Biochem Cell Biol 36:2503–2518

    Article  PubMed  CAS  Google Scholar 

  37. Aerts JM, Ottenhoff R, Powlson AS, Grefhorst A, van Eijk M, Dubbelhuis PF, Aten J, Kuipers F, Serlie MJ, Wennekes T et al (2007) Pharmacological inhibition of glucosylceramide synthase enhances insulin sensitivity. Diabetes 56:1341–1349

    Article  PubMed  CAS  Google Scholar 

  38. Ardail D, Popa I, Alcantara K, Pons A, Zanetta JP, Louisot P, Thomas L, Portoukalian J (2001) Occurrence of ceramides and neutral glycolipids with unusual long-chain base composition in purified rat liver mitochondria. FEBS Lett 488:160–164

    Article  PubMed  CAS  Google Scholar 

  39. Strasberg P (1986) Cerebrosides and psychosine disrupt mitochondrial functions. Biochem Cell Biol 64:485–489

    Article  PubMed  CAS  Google Scholar 

  40. Ljubicic V, Hood DA (2008) Kinase-specific responsiveness to incremental contractile activity in skeletal muscle with low and high mitochondrial content. Am J Physiol Endocrinol Metab 295:E195–E204

    Article  PubMed  CAS  Google Scholar 

  41. Nair KS, Bigelow ML, Asmann YW, Chow LS, Coenen-Schimke JM, Klaus KA, Guo ZK, Sreekumar R, Irving BA (2008) Asian Indians have enhanced skeletal muscle mitochondrial capacity to produce ATP in association with severe insulin resistance. Diabetes 57:1166–1175

    Article  PubMed  CAS  Google Scholar 

  42. Boushel R, Gnaiger E, Schjerling P, Skovbro M, Kraunsoe R, Dela F (2007) Patients with type 2 diabetes have normal mitochondrial function in skeletal muscle. Diabetologia 50:790–796

    Article  PubMed  CAS  Google Scholar 

  43. Rabol R, Hojberg PM, Almdal T, Boushel R, Haugaard SB, Madsbad S, Dela F (2009) Effect of hyperglycemia on mitochondrial respiration in type 2 diabetes. J Clin Endocrinol Metab 94:1372–1378

    Article  PubMed  Google Scholar 

  44. Turner N, Bruce CR, Beale SM, Hoehn KL, So T, Rolph MS, Cooney GJ (2007) Excess lipid availability increases mitochondrial fatty acid oxidative capacity in muscle: evidence against a role for reduced fatty acid oxidation in lipid-induced insulin resistance in rodents. Diabetes 56:2085–2092

    Article  PubMed  CAS  Google Scholar 

  45. Hancock CR, Han DH, Chen M, Terada S, Yasuda T, Wright DC, Holloszy JO (2008) High-fat diets cause insulin resistance despite an increase in muscle mitochondria. Proc Natl Acad Sci USA 105:7815–7820

    Article  PubMed  CAS  Google Scholar 

  46. Bonen A, Holloway GP, Tandon NN, Han XX, McFarlan JT, Glatz JF, Luiken JJ (2009) Cardiac and skeletal muscle fatty acid transport and transporters, triacylglycerol and fatty acid oxidation in lean and Zucker diabetic fatty (ZDF) rats. Am J Physiol 297:R1202–R1212

    Article  CAS  Google Scholar 

  47. Ogata T, Yamasaki Y (1997) Ultra-high-resolution scanning electron microscopy of mitochondria and sarcoplasmic reticulum arrangement in human red, white, and intermediate muscle fibers. Anat Rec 248:214–223

    Article  PubMed  CAS  Google Scholar 

  48. Gollnick PD, Sjodin B, Karlsson J, Jansson E, Saltin B (1974) Human soleus muscle: a comparison of fiber composition and enzyme activities with other leg muscles. Pflugers Arch 348:247–255

    Article  PubMed  CAS  Google Scholar 

  49. Yechoor VK, Patti ME, Ueki K, Laustsen PG, Saccone R, Rauniyar R, Kahn CR (2004) Distinct pathways of insulin-regulated versus diabetes-regulated gene expression: an in vivo analysis in MIRKO mice. Proc Natl Acad Sci USA 101:16525–16530

    Article  PubMed  CAS  Google Scholar 

  50. Stump CS, Short KR, Bigelow ML, Schimke JM, Nair KS (2003) Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts. Proc Natl Acad Sci USA 100:7996–8001

    Article  PubMed  CAS  Google Scholar 

  51. Karakelides H, Asmann YW, Bigelow ML, Short KR, Dhatariya K, Coenen-Schimke J, Kahl J, Mukhopadhyay D, Nair KS (2007) Effect of insulin deprivation on muscle mitochondrial ATP production and gene transcript levels in type 1 diabetic subjects. Diabetes 56:2683–2689

    Article  PubMed  CAS  Google Scholar 

  52. Sleigh A, Raymond-Barker P, Thackray K, Porter D, Hatunic M, Vottero A, Burren C, Mitchell C, McIntyre M, Brage S et al (2011) Mitochondrial dysfunction in patients with primary congenital insulin resistance. J Clin Invest 121:2457–2461

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We acknowledge Puk Andreasen and Benjamin August (Taconic Europe, Lille Skensved, Denmark) for sharing data on blood sugar values of old ob/ob mice and Dr. Martin Hellmich (Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne) for advice with statistical analyses. Prof. Jens Brüning (Department of Mouse Genetics and Metabolism, University of Cologne) provided MCK-Cre and InsR-loxP mice and Maria Bust, Alexander Müller, and Olivia Kawaletz provided excellent technical assistance. This work was funded by Köln Fortune (WK, MS, RJW), Center for Molecular Medicine Cologne (JCvKR), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (WK, MS, RJW).

Disclosure statement

The authors declare that there is no conflict of interest associated with this manuscript.

Author information

Author notes

  1. A. Franko

    Present address: Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstaedter Landstr. 1, 85764, Neuherberg, Germany

Authors and Affiliations

  1. Institute for Vegetative Physiology, University of Cologne, 50931, Cologne, Germany

    A. Franko, J. C. von Kleist-Retzow, M. Böse & R. J. Wiesner

  2. Center for Molecular Medicine Cologne, CMMC, University of Cologne, 50931, Cologne, Germany

    J. C. von Kleist-Retzow, W. Krone, M. Schubert & R. J. Wiesner

  3. Department of Pediatrics, University of Cologne, 50924, Cologne, Germany

    J. C. von Kleist-Retzow

  4. Department of Mouse Genetics and Metabolism, Institute for Genetics, University of Cologne, 50674, Cologne, Germany

    C. Sanchez-Lasheras

  5. Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, 50935, Cologne, Germany

    S. Brodesser & O. Krut

  6. Department of Epileptology, University Bonn Medical Center, 53105, Bonn, Germany

    W. S. Kunz

  7. Max-Planck-Institute for Neurological Research with Klaus-Joachim-Zülch-Laboratories of the Max Planck Society, Faculty of Medicine, University of Cologne, 50931, Cologne, Germany

    D. Wiedermann & M. Hoehn

  8. Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University of Cologne, 50937, Cologne, Germany

    O. Stöhr, L. Moll, S. Freude, W. Krone & M. Schubert

  9. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), 50674, Cologne, Germany

    W. Krone, M. Schubert & R. J. Wiesner

Authors
  1. A. Franko
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. C. von Kleist-Retzow
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Böse
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. Sanchez-Lasheras
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. Brodesser
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. O. Krut
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. W. S. Kunz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. D. Wiedermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M. Hoehn
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. O. Stöhr
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. L. Moll
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. S. Freude
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. W. Krone
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. M. Schubert
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. R. J. Wiesner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to M. Schubert or R. J. Wiesner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Franko, A., von Kleist-Retzow, J.C., Böse, M. et al. Complete failure of insulin-transmitted signaling, but not obesity-induced insulin resistance, impairs respiratory chain function in muscle. J Mol Med 90, 1145–1160 (2012). https://doi.org/10.1007/s00109-012-0887-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-012-0887-y

Keywords

Search

Navigation