Skip to main content
Log in

Role of adiponectin in the metabolism of skeletal muscles in collagen VI–related myopathies

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

Abstract

The role of adiponectin has been particularly deepened in diabetic muscles while the study of adiponectin in hereditary myopathies has been marginally investigated. Here, we report the study about adiponectin effects in Col6a1−/− (collagen VI–null) mice. Col6a1−/− mice show myophatic phenotype closer to that of patients with Bethlem myopathy, thus representing an excellent animal model for the study of this hereditary disease. Our findings demonstrate that Col6a1−/− mice have decreased plasma adiponectin content and diseased myoblasts have an impaired autocrine secretion of the hormone. Moreover, Col6a1−/− myoblasts show decreased glucose uptake and mitochondria with depolarized membrane potential and impaired functionality, as supported by decreased oxygen consumption. Exogenous addition of globular adiponectin modifies the features of Col6a1−/− myoblasts, becoming closer to that of the healthy myoblasts. Indeed, globular adiponectin enhances glucose uptake in Col6a1−/− myoblasts, modifies mitochondrial membrane potential, and restores oxygen consumption, turning closer to those of wild-type myoblasts. Finally, increase of plasma adiponectin level in Col6a1−/− mice is induced by fasting, a condition that has been previously shown to lead to the amelioration of the dystrophic phenotype. Collectively, our results demonstrate that exogenous replenishment of adiponectin reverses metabolic abnormalities observed in Col6a1−/− myoblasts.

Key messages

  • Col6a1−/− mice have decreased level of plasma adiponectin.

  • Myoblasts from Col6a1−/− muscles have impaired local adiponectin secretion.

  • Col6a1−/− myoblasts reveal altered metabolic features.

  • Addition of exogenous adiponectin ameliorates Col6a1−/− metabolic features.

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

Access this article

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

Similar content being viewed by others

References

  1. Lampe AK, Bushby KM (2005) Collagen VI related muscle disorders. J Med Genet 42:673–685

    Article  CAS  Google Scholar 

  2. Bonaldo P, Braghetta P, Zanetti M, Piccolo S, Volpin D, Bressan GM (1998) Collagen VI deficiency induces early onset myopathy in the mouse: an animal model for Bethlem myopathy. Hum Mol Genet 7:2135–2140

    Article  CAS  Google Scholar 

  3. Grumati P, Coletto L, Sabatelli P, Cescon M, Angelin A, Bertaggia E, Blaauw B, Urciuolo A, Tiepolo T, Merlini L, Maraldi NM, Bernardi P, Sandri M, Bonaldo P (2010) Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration. Nat Med 16:1313–1320

    Article  CAS  Google Scholar 

  4. Chrisam M, Pirozzi M, Castagnaro S, Blaauw B, Polishchuck R, Cecconi F, Grumati P, Bonaldo P (2015) Reactivation of autophagy by spermidine ameliorates the myopathic defects of collagen VI-null mice. Autophagy 11:2142–2152

    Article  CAS  Google Scholar 

  5. Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, Froguel P, Foufelle F, Ferre P, Carling D, Kimura S, Nagai R, Kahn BB, Kadowaki T (2002) Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 8:1288–1295

    Article  CAS  Google Scholar 

  6. Fruebis J, Tsao TS, Javorschi S, Ebbets-Reed D, Erickson MR, Yen FT, Bihain BE, Lodish HF (2001) Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci U S A 98:2005–2010

    Article  CAS  Google Scholar 

  7. Yamauchi T, Iwabu M, Okada-Iwabu M, Kadowaki T (2014) Adiponectin receptors: a review of their structure, function and how they work. Best Pract Res Clin Endocrinol Metab 28:15–23

    Article  CAS  Google Scholar 

  8. Fiaschi T, Giannoni E, Taddei ML, Chiarugi P (2012) Globular adiponectin activates motility and regenerative traits of muscle satellite cells. PLoS One 7:e34782. https://doi.org/10.1371/journal.pone.0034782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Fiaschi T, Cirelli D, Comito G, Gelmini S, Ramponi G, Serio M, Chiarugi P (2009) Globular adiponectin induces differentiation and fusion of skeletal muscle cells. Cell Res 19:584–597

    Article  CAS  Google Scholar 

  10. Gamberi T, Modesti A, Magherini F, D’Souza DM, Hawke T, Fiaschi T (2016) Activation of autophagy by globular adiponectin is required for muscle differentiation. Biochim Biophys Acta 1863:694–702

    Article  CAS  Google Scholar 

  11. Fiaschi T, Magherini F, Gamberi T, Modesti PA, Modesti A (2014) Adiponectin as a tissue regenerating hormone: more than a metabolic function. Cell Mol Life Sci 71:1917–1925

    Article  CAS  Google Scholar 

  12. Wang ZV, Scherer PE (2016) Adiponectin, the past two decades. J Mol Cell Biol 8:93–100

    Article  CAS  Google Scholar 

  13. Rando TA, Blau HM (1994) Primary mouse myoblast purification, characterization, and transplantation for cell-mediated gene therapy. J Cell Biol 125:1275–1287

    Article  CAS  Google Scholar 

  14. Gamberi T, Fiaschi T, Valocchia E, Modesti A, Mantuano P, Rolland JF, Sanarica F, De Luca A, Magherini F (2018) Proteome analysis in dystrophic mdx mouse muscle reveals a drastic alteration of key metabolic and contractile proteins after chronic exercise and the potential modulation by anti-oxidant compounds. J Proteome 170:43–58

    Article  CAS  Google Scholar 

  15. De Palma S, Leone R, Grumati P, Vasso M, Polishchuk R, Capitanio D, Braghetta P, Bernardi P, Bonaldo P, Gelfi C (2013) Changes in muscle cell metabolism and mechanotransduction are associated with myopathic phenotype in a mouse model of collagen VI deficiency. PLoS One 8:e56716. https://doi.org/10.1371/journal.pone.0056716

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ceddia RB, Somwar R, Maida A, Fang X, Bikopoulos G, Sweeney G (2005) Globular adiponectin increases GLUT4 translocation and glucose uptake but reduces glycogen synthesis in rat skeletal muscle cells. Diabetologia 48:132–139

    Article  CAS  Google Scholar 

  17. Iwabu M, Yamauchi T, Okada-Iwabu M, Sato K, Nakagawa T, Funata M, Yamaguchi M, Namiki S, Nakayama R, Tabata M, Ogata H, Kubota N, Takamoto I, Hayashi YK, Yamauchi N, Waki H, Fukayama M, Nishino I, Tokuyama K, Ueki K, Oike Y, Ishii S, Hirose K, Shimizu T, Touhara K, Kadowaki T (2010) Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) and AMPK/SIRT1. Nature 464:1313–1319

    Article  CAS  Google Scholar 

  18. Kadowaki T, Yamauchi T, Kubota N (2008) The physiological and pathophysiological role of adiponectin and adiponectin receptors in the peripheral tissues and CNS. FEBS Lett 582:74–80

    Article  CAS  Google Scholar 

  19. Hathout Y, Marathi RL, Rayavarapu S, Zhang A, Brown KJ, Seol H, Gordish-Dressman H, Cirak S, Bello L, Nagaraju K, Partridge T, Hoffman EP, Takeda S’, Mah JK, Henricson E, McDonald C (2014) Discovery of serum protein biomarkers in the mdx mouse model and cross-species comparison to Duchenne muscular dystrophy patients. Hum Mol Genet 23:6458–6469

    Article  CAS  Google Scholar 

  20. Jin D, Sun J, Huang J, Yu X, Yu A, He Y, Li Q, Yang Z (2015) Peroxisome proliferator-activated receptor γ enhances adiponectin secretion via up-regulating DsbA-L expression. Mol Cell Endocrinol 411:97–104

    Article  CAS  Google Scholar 

  21. He Y, Lu L, Wei X, Jin D, Qian T, Yu A, Sun J, Cui J, Yang Z (2016) The multimerization and secretion of adiponectin are regulated by TNF-alpha. Endocrine 51:456–468

    Article  CAS  Google Scholar 

  22. DeClercq V, d’Eon B, McLeod RS (2015) Fatty acids increase adiponectin secretion through both classical and exosome pathways. Biochim Biophys Acta 1851:1123–1133

    Article  CAS  Google Scholar 

  23. Tang H, Sebastian BM, Axhemi A, Chen X, Hillian AD, Jacobsen DW, Nagy LE (2012) Ethanol-induced oxidative stress via the CYP2E1 pathway disrupts adiponectin secretion from adipocytes. Alcohol Clin Exp Res 36:214–222

    Article  CAS  Google Scholar 

  24. Parola M, Marra F (2011) Adipokines and redox signaling: impact on fatty liver disease. Antioxid Redox Signal 15:461–483

    Article  CAS  Google Scholar 

  25. Rando TA, Disatnik MH, Yu Y, Franco A (1998) Muscle cells from mdx mice have an increased susceptibility to oxidative stress. Neuromuscul Disord 8:14–21

    Article  CAS  Google Scholar 

  26. Whitehead NP, Yeung EW, Allen DG (2006) Muscle damage in mdx (dystrophic) mice: role of calcium and reactive oxygen species. Clin Exp Pharmacol Physiol 33:657–662

    Article  CAS  Google Scholar 

  27. Tidball JG, Wehling-Henricks M (2007) The role of free radicals in the pathophysiology of muscular dystrophy. J Appl Physiol (1985) 102:1677–1686

    Article  CAS  Google Scholar 

  28. Menazza S, Blaauw B, Tiepolo T, Toniolo L, Braghetta P, Spolaore B, Reggiani C, Di Lisa F, Bonaldo P, Canton M (2010) Oxidative stress by monoamine oxidases is causally involved in myofiber damage in muscular dystrophy. Hum Mol Genet 19:4207–4215

    Article  CAS  Google Scholar 

  29. Khan T, Muise ES, Iyengar P, Wang ZV, Chandalia M, Abate N, Zhang BB, Bonaldo P, Chua S, Scherer PE (2009) Metabolic dysregulation and adipose tissue fibrosis: role of collagen VI. Mol Cell Biol 29:1575–1591

    Article  CAS  Google Scholar 

  30. Le A, Lane AN, Hamaker M, Bose S, Gouw A, Barbi J, Tsukamoto T, Rojas CJ, Slusher BS, Zhang H et al (2012) Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab 15:110–121

    Article  CAS  Google Scholar 

  31. Wise DR, Ward PS, Shay JE, Cross JR, Gruber JJ, Sachdeva UM, Platt JM, DeMatteo RG, Simon MC, Thompson CB (2011) Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability. Proc Natl Acad Sci U S A 108:19611–19616

    Article  CAS  Google Scholar 

  32. Fiaschi T, Tedesco FS, Giannoni E, Diaz-Manera J, Parri M, Cossu G, Chiarugi P (2010) Globular adiponectin as a complete mesoangioblast regulator: role in proliferation, survival, motility, and skeletal muscle differentiation. Mol Biol Cell 21:848–859

    Article  CAS  Google Scholar 

  33. Yoon MJ, Lee GY, Chung JJ, Ahn YH, Hong SH, Kim JB (2006) Adiponectin increases fatty acid oxidation in skeletal muscle cells by sequential activation of AMP-activated protein kinase, p38 mitogen-activated protein kinase, and peroxisome proliferator-activated receptor alpha. Diabetes 55:2562–2570

    Article  CAS  Google Scholar 

  34. Kubota N, Yano W, Kubota T, Yamauchi T, Itoh S, Kumagai H, Kozono H, Takamoto I, Okamoto S, Shiuchi T, Suzuki R, Satoh H, Tsuchida A, Moroi M, Sugi K, Noda T, Ebinuma H, Ueta Y, Kondo T, Araki E, Ezaki O, Nagai R, Tobe K, Terauchi Y, Ueki K, Minokoshi Y, Kadowaki T (2007) Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. Cell Metab 6:55–68

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported by the Italian Ministry of University and Research (MIUR).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Tania Fiaschi.

Ethics declarations

Mouse procedures were approved by the Ethics Committee of the University of Padua and authorized by the Italian Ministry of Health according to D. Lgs. 26/2014 implementing Directive 2010/63/EU.

Conflict of interest

The authors declare that they no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Supplementary figure 1

Analysis of adiponectin in females ofCol6a1–/–mice. A) Plasma adiponectin level obtained using ELISA test and reported as percentage of decrease of Col6a1–/– in comparison to WT. n=5 mice/group. *p<0.01; acrp30: adiponectin. B) Intracellular level of adiponectin in diaphragm and tibialis anterior by immunoblot. GAPDH immunoblot has been used for normalization. Bar graphs show the expression level of adiponectin reported as arbitrary unit (a.u.). (PNG 56 kb)

MOESM1

High Resolution Image (TIF 545 kb)

Supplementary figure 2.

Confocal images of myoblasts isolated from diaphragm of WT and Col6a1–/– mice incubated with (right panel), or without (left panel) gAd (1 μg/ml) for 30 minutes. The intracellular location of GLUT4 is shown as green signal obtained using a specific primary anti-GLUT4 antibody (ThermoFisher Scientific) and a secondary antibody conjugated to Alexa-488. Nuclei have been labelled with DAPI. The images are representative of three independent experiments. gAd: globular adiponectin. (PNG 242 kb)

MOESM1

High Resolution Image (TIF 1615 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gamberi, T., Magherini, F., Mannelli, M. et al. Role of adiponectin in the metabolism of skeletal muscles in collagen VI–related myopathies. J Mol Med 97, 793–801 (2019). https://doi.org/10.1007/s00109-019-01766-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-019-01766-0

Keywords

Navigation