SpringerLink
Log in

PGC-1α–FNDC5–BDNF signaling pathway in skeletal muscle confers resilience to stress in mice subjected to chronic social defeat

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Skeletal muscle consumes two thirds of the body’s energy and may play a role in stress-related disorders. Evidence suggests that the peroxisome proliferator-activated receptor γ coactivator α (PGC-1α)–fibronectin type III domain-containing 5 (FNDC5)–brain-derived neurotrophic factor (BDNF) signaling pathway in skeletal muscle plays a key role in conferring the beneficial effects of exercise. In this study, we aimed to determine whether this pathway contributes to the resilience or susceptibility of mice subjected to chronic social defeat stress (CSDS). BDNF–tropomyosin receptor kinase B (TrkB) and proBDNF–p75NTR signaling in the medial prefrontal cortex and nucleus accumbens of susceptible but not resilient mice were significantly altered compared with the controls. Furthermore, the levels of PGC-1α, FNDC5, and BDNF, as well as the p-TrkB/TrkB ratio in the skeletal muscle of susceptible but not resilient mice, were significantly lower than those of the controls, but the levels of proBDNF and p75NTR in the skeletal muscle of susceptible mice were significantly higher than those of the controls. Moreover, there were significant positive associations between social interaction test data and the expression of PGC-1α, FNDC5, and BDNF or the p-TrkB/TrkB ratio in skeletal muscle. These results suggest that the downregulation of the PGC-1α–FNDC5–BDNF signaling pathway in skeletal muscle contributes to resilience vs. susceptibility to CSDS. Therefore, alterations in this pathway in skeletal muscle may play a crucial role in mediating stress-related disorders.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (France)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Agudelo LZ, Femenia T, Orhan F, Porsmyr-Palmertz M, Goiny M, Martinez-Redondo V, Correia JC, Izadi M, Bhat M, Schuppe-Koistinen I, Pettersson AT, Ferreira DMS, Krook A, Barres R, Zierath JR, Erhardt S, Lindskog M, Ruas JL (2014) Skeletal muscle PGC-1alpha1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. Cell 159:33–45

    Article  CAS  Google Scholar 

  • Azimi M, Gharakhanlou R, Naghdi N, Khodadadi D, Heysieattalab S (2018) Moderate treadmill exercise ameliorates amyloid-beta-induced learning and memory impairment, possibly via increasing AMPK activity and up-regulation of the PGC-1alpha/FNDC5/BDNF pathway. Peptides 102:78–88

    Article  CAS  Google Scholar 

  • Baskin KK, Winders BR, Olson EN (2015) Muscle as a “mediator” of systemic metabolism. Cell Metab 21:237–248

    Article  CAS  Google Scholar 

  • Bjorkholm C, Monteggia LM (2016) BDNF - a key transducer of antidepressant effects. Neuropharmacology 102:72–79

    Article  Google Scholar 

  • Duman RS, Monteggia LM (2006) A neurotrophic model for stress-related mood disorders. Biol Psychiatry 59:1116–1127

    Article  CAS  Google Scholar 

  • Erickson HP (2013) Irisin and FNDC5 in retrospect: an exercise hormone or a transmembrane receptor? Adipocyte 2:289–293

    Article  CAS  Google Scholar 

  • Feder A, Nestler EJ, Charney DS (2009) Psychobiology and molecular genetics of resilience. Nat Rev Neurosci 10:446–457

    Article  CAS  Google Scholar 

  • Franklin TB, Saab BJ, Mansuy IM (2012) Neural mechanisms of stress resilience and vulnerability. Neuron 75:747–761

    Article  CAS  Google Scholar 

  • Hall KD, Heymsfield SB, Kemnitz JW, Klein S, Schoeller DA, Speakman JR (2012) Energy balance and its components: implications for body weight regulation. Am J Clin Nutr 95:989–994

    Article  Google Scholar 

  • Hashimoto K (2010) Brain-derived neurotrophic factor as a biomarker for mood disorders: an historical overview and future directions. Psychiatry Clin Neurosci 64:341–357

    Article  CAS  Google Scholar 

  • Hashimoto K, Shimizu E, Iyo M (2004) Critical role of brain-derived neurotrophic factor in mood disorders. Brain Res Brain Res Rev 45:104–114

    Article  CAS  Google Scholar 

  • Hoppeler H (2016) Molecular networks in skeletal muscle plasticity. J Exp Biol 219:205–213

    Article  Google Scholar 

  • Ieraci A, Madaio AI, Mallei A, Lee FS, Popoli M (2016) Brain-derived neurotrophic factor Val66Met human polymorphism impairs the beneficial exercise-induced neurobiological changes in mice. Neuropsychopharmacology 41:3070–3079

    Article  CAS  Google Scholar 

  • Kennedy B, Fang F, Valdimarsdottir U, Udumyan R, Montgomery S, Fall K (2017) Stress resilience and cancer risk: a nationwide cohort study. J Epidemiol Community Health 71:947–953

    Article  Google Scholar 

  • Krishnan V, Han MH, Graham DL, Berton O, Renthal W, Russo SJ, Laplant Q, Graham A, Lutter M, Lagace DC, Ghose S, Reister R, Tannous P, Green TA, Neve RL, Chakravarty S, Kumar A, Eisch AJ, Self DW, Lee FS, Tamminga CA, Cooper DC, Gershenfeld HK, Nestler EJ (2007) Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell 131:391–404

    Article  CAS  Google Scholar 

  • Lee HW, Ahmad M, Wang HW, Leenen FH (2017) Effects of exercise training on brain-derived neurotrophic factor in skeletal muscle and heart of rats post myocardial infarction. Exp Physiol 102:314–328

    Article  CAS  Google Scholar 

  • Lindholm JS, Castren E (2014) Mice with altered BDNF signaling as models for mood disorders and antidepressant effects. Front Behav Neurosci 8:143

    Article  Google Scholar 

  • Matthews VB, Astrom MB, Chan MH, Bruce CR, Krabbe KS, Prelovsek O, Akerstrom T, Yfanti C, Broholm C, Mortensen OH, Penkowa M, Hojman P, Zankari A, Watt MJ, Bruunsgaard H, Pedersen BK, Febbraio MA (2009) Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase. Diabetologia 52:1409–1418

    Article  CAS  Google Scholar 

  • Nestler EJ, Carlezon WA Jr (2006) The mesolimbic dopamine reward circuit in depression. Biol Psychiatry 59:1151–1159

    Article  CAS  Google Scholar 

  • Nestler EJ, Barrot M, DiLeone RJ, Eisch AJ, Gold SJ, Monteggia LM (2002) Neurobiology of depression. Neuron 34:13–25

    Article  CAS  Google Scholar 

  • Ohgi Y, Futamura T, Hashimoto K (2015) Glutamate signaling in synaptogenesis and NMDA receptors as potential therapeutic targets for psychiatric disorders. Curr Mol Med 15:206–221

    Article  CAS  Google Scholar 

  • Pedersen BK, Febbraio MA (2012) Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol 8:457–465

    Article  CAS  Google Scholar 

  • Pilegaard H, Saltin B, Neufer PD (2003) Exercise induces transient transcriptional activation of the PGC-1alpha gene in human skeletal muscle. J Physiol 546:851–858

    Article  CAS  Google Scholar 

  • Puigserver P, Adelmant G, Wu Z, Fan M, Xu J, O'Malley B, Spiegelman BM (1999) Activation of PPARgamma coactivator-1 through transcription factor docking. Science 286:1368–1371

    Article  CAS  Google Scholar 

  • Qu Y, Yang C, Ren Q, Ma M, Dong C, Hashimoto K (2018) Regional differences in dendritic spine density confer resilience to chronic social defeat stress. Acta Neuropsychiatr 30:117–122

    Article  Google Scholar 

  • Ren Q, Ma M, Yang C, Zhang JC, Yao W, Hashimoto K (2015) BDNF-TrkB signaling in the nucleus accumbens shell of mice has key role in methamphetamine withdrawal symptoms. Transl Psychiatry 5:e666

    Article  CAS  Google Scholar 

  • Rolfe DF, Brown GC (1997) Cellular energy utilization and molecular origin of standard metabolic rate in mammals. Physiol Rev 77:731–758

    Article  CAS  Google Scholar 

  • Shimizu E, Hashimoto K, Iyo M (2004) Ethnic difference of the BDNF 196G/A (val66met) polymorphism frequencies: the possibility to explain ethnic mental traits. Am J Med Genet B Neuropsychiatr Genet 126B:122–123

    Article  Google Scholar 

  • Shirayama Y, Yang C, Zhang JC, Ren Q, Yao W, Hashimoto K (2015) Alterations in brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in the brain regions of a learned helplessness rat model and the antidepressant effects of a TrkB agonist and antagonist. Eur Neuropsychopharmacol 25:2449–2458

    Article  CAS  Google Scholar 

  • Southwick SM, Charney DS (2012) The science of resilience: implications for the prevention and treatment of depression. Science 338:79–82

    Article  CAS  Google Scholar 

  • Stephens FB (2018) Does skeletal muscle carnitine availability influence fuel selection during exercise? Proc Nutr Soc 77:11–19

    Article  CAS  Google Scholar 

  • Westerblad H, Bruton JD, Katz A (2010) Skeletal muscle: energy metabolism, fiber types, fatigue and adaptability. Exp Cell Res 316:3093–3099

    Article  CAS  Google Scholar 

  • Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D, Wu J, Ma D, Lin JD, Greenberg ME, Spiegelman BM (2013) Exercise induces hippocampal BDNF through a PGC-1alpha/FNDC5 pathway. Cell Metab 18:649–659

    Article  CAS  Google Scholar 

  • Yang C, Shirayama Y, Zhang JC, Ren Q, Hashimoto K (2015a) Regional differences in brain-derived neurotrophic factor levels and dendritic spine density confer resilience to inescapable stress. Int J Neuropsychopharmacol 18:pyu121

    Article  Google Scholar 

  • Yang C, Shirayama Y, Zhang JC, Ren Q, Yao W, Ma W, Dong C, Hashimoto K (2015b) R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects. Transl Psychiatry 5:e632

    Article  CAS  Google Scholar 

  • Yang B, Yang C, Ren Q, Zhang JC, Chen QX, Shirayama Y, Hashimoto K (2016) Regional differences in the expression of brain-derived neurotrophic factor (BDNF) pro-peptide, proBDNF and preproBDNF in the brain confer stress resilience. Eur Arch Psychiatry Clin Neurosci 266:765–769

    Article  Google Scholar 

  • Yang C, Qu Y, Fujita Y, Ren Q, Ma M, Dong C, Hashimoto K (2017a) Possible role of the gut microbiota-brain axis in the antidepressant effects of (R)-ketamine in a social defeat stress model. Transl Psychiatry 7:1294

    Article  Google Scholar 

  • Yang B, Ren Q, Zhang JC, Chen QX, Hashimoto K (2017b) Altered expression of BDNF, BDNF pro-peptide and their precursor proBDNF in brain and liver tissues from psychiatric disorders: rethinking the brain-liver axis. Transl Psychiatry 7:e1128

    Article  CAS  Google Scholar 

  • Yang C, Ren Q, Qu Y, Zhang JC, Ma M, Dong C, Hashimoto K (2018) Mechanistic target of rapamycin-independent antidepressant effects of (R)-ketamine in a social defeat stress model. Biol Psychiatry 83:18–28

    Article  CAS  Google Scholar 

  • Yu T, Chang Y, Gao XL, Li H, Zhao P (2017) Dynamic expression and the role of BDNF in exercise-induced skeletal muscle regeneration. Int J Sports Med 38:959–966

    Article  CAS  Google Scholar 

  • Zhang JC, Wu J, Fujita Y, Yao W, Ren Q, Yang C, Li SX, Shirayama Y, Hashimoto K (2014) Antidepressant effects of TrkB ligands on depression-like behavior and dendritic changes in mice after inflammation. Int J Neuropsychopharmacol 2014:18

  • Zhang JC, Yao W, Hashimoto K (2016) Brain-derived neurotrophic factor (BDNF)-TrkB signaling in inflammation-related depression and potential therapeutic targets. Curr Neuropharmacol 14:721–731

    Article  CAS  Google Scholar 

Download references

Funding

This study was supported by grants from National Natural Science Foundation of China [No. 81703482 (to C.Y.), No. 81500931 (to J.Z.), and No. 81571047 and 81771159 (to A.L.)].

Author information

Author notes

  1. Gaofeng Zhan and Niannian Huang contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Avenue, Wuhan, China

    Gaofeng Zhan, Niannian Huang, Shan Li, Dongyu Hua, Jie Zhang, ** Fang, Ning Yang, Ailin Luo & Chun Yang

Authors
  1. Gaofeng Zhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Niannian Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dongyu Hua
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jie Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. ** Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ning Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ailin Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Chun Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ailin Luo or Chun Yang.

Ethics declarations

Procedures of this animal experiment were in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals. The experimental protocols were approved by the Experimental Animal Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology (Wuhan, China).

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhan, G., Huang, N., Li, S. et al. PGC-1α–FNDC5–BDNF signaling pathway in skeletal muscle confers resilience to stress in mice subjected to chronic social defeat. Psychopharmacology 235, 3351–3358 (2018). https://doi.org/10.1007/s00213-018-5041-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-018-5041-2

Keywords

Search

Navigation