Skip to main content

The influence of isoflavone for denervation-induced muscle atrophy



Decrease in activity stress induces skeletal muscle atrophy. A previous study showed that treatment with a high level (20%) of isoflavone inhibits muscle atrophy after short-term denervation (at 4 days) in mice. The present study was designed to elucidate whether the dietary isoflavone aglycone (AglyMax) at a 0.6% prevents denervation-mediated muscle atrophy, based on the modulation of atrogin-1- or apoptosis-dependent signaling.


Mice were fed either a normal diet or 0.6% AglyMax diet. One week later, the right sciatic nerve was cut. The wet weight, mean fiber area, amount of atrogin-1 and cleaved caspase-3 proteins, and the percentages of apoptotic nuclei were examined in the gastrocnemius muscle at 14 days after denervation.


The 0.6% AglyMax diet significantly attenuated denervation-induced decreases in fiber atrophy but not the muscle wet weight. In addition, dietary isoflavone suppressed the denervation-induced apoptosis in spite of there being no significant changes in the amount of cleaved caspase-3 protein. In contrast, the 0.6% AglyMax diet did not significantly modulate the protein expression of atrogin-1 in the denervated muscle of mice.


The isoflavone aglycone (AglyMax) at a 0.6% significantly would modulate muscle atrophy after denervation in mice, probably due to the decrease in apoptosis-dependent signaling.

This is a preview of subscription content, access via your institution.

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


  1. Sakuma K, Yamaguchi A (2015) Sarcopenia and its intervention. In: Yu BP (ed) Nutrition, exercise and epigenetics: ageing interventions. Springer, Berlin, pp 127–152

    Google Scholar 

  2. Sakuma K, Yamaguchi A (2010) Molecular mechanisms in aging and current strategies to counteract sarcopenia. Curr Aging Sci 3(2):90–101

    Article  CAS  PubMed  Google Scholar 

  3. Camerino GM, Desaphy JF, De Bellis M, Capogrosso RF, Cozzoli A, Dinardo MM, Caloiero R, Musaraj K, Fonzino A, Conte E, Jagerschmidt C, Namour F, Liantonio A, De Luca A, Conte Camerino D, Pierno S (2015) Effects of nandrolone in the counteraction of skeletal muscle atrophy in a mouse model of muscle disuse: molecular biology and functional evaluation. PLoS One 10(6):e0129686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Qin W, Pan J, Wu Y, Bauman WA, Cardozo C (2015) Anabolic steroids activate calcineurin-NFAT signaling and thereby increase myotube size and reduce denervation atrophy. Mol Cell Endocrinol 399:336–345

    Article  CAS  Google Scholar 

  5. Becker C, Lord SR, Studenski SA, Warden SJ, Fielding RA, Recknor CP, Hochberg MC, Ferrari SL, Blain H, Binder EF, Rolland Y, Poiraudeau S, Benson CT, Myers SL, Hu L, Ahmad QI, Pacuch KR, Gomez EV, Benichou O, STEADY Group (2015) Myostatin antibody (LY2495655) in older weak fallers: a proof-of-concept, randomised, phase 2 trial. Lancet Diabetes Endocrinol 3(12):948–957

    Article  CAS  PubMed  Google Scholar 

  6. Phillips SM (2015) Nutritional supplements in support of resistance exercise to counter age-related sarcopenia. Adv Nutr 6(4):452–460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sakuma K, Yamaguchi A (2015) An overview of the therapeuticc strategies for preventing sarcopenia. In: Sakuma K (ed) Basic biology and current understanding of skeletal muscle. Nova Science Publishers, Hauppauge, pp 87–122

    Google Scholar 

  8. Thomas DK, Quinn MA, Saunders DH, Creig CA (2016) Protein supplementation does not significantly augment the effects of resistance exercise training in older adults: a systematic review. J Am Med Dir Assoc 17(10):959.e1–959.e9

    Article  Google Scholar 

  9. Tham DM, Gardner CD, Haskell WL (1998) Clinical review 97: potential health benefits of dietary phytoestrogens: a review of the clinical, epidemiological, and mechanistic evidence. J Clin Endocrinol Metab 83(7):2223–2235

    CAS  PubMed  Google Scholar 

  10. Beekmann K, de Haan LH, Actis GL, Houtman R, van Bladeren PJ, Rietjens IM (2015) The effect of glucuronidation on isoflavone induced estrogen receptor (ER) α and ERβ mediated coregulator interactions. J Steroid Biochem Mol Biol 154:245–253

    Article  CAS  PubMed  Google Scholar 

  11. Kurrat A, Blei T, Kluxen FM, Mueller DR, Piechotta M, Soukup ST, Kulling SE, Diel P (2015) Lifelong exposure to dietary isoflavones reduces risk of obesity in ovariectomized Wistar rats. Mol Nutr Food Res 59(12):2407–2418

    Article  CAS  PubMed  Google Scholar 

  12. Abe T, Kohno S, Yama T, Ochi A, Suto T, Hirasaka K, Ohno A, Teshima-Kondo S, Okumura Y, Oarada M, Choi I, Mukai R, Terao J, Nikawa T (2013) Soy glycinin contains a functional inhibitory sequence against muscle-atrophy-associated ubiquitin ligase Cbl-b. Int J Endocrinol 2013:907565

    PubMed  PubMed Central  Google Scholar 

  13. Reagan-Shaw S, Nihal M, Ahmad N (2008) Does translation from animals to human studies revisited. FASEB J 22(3):659–661

    Article  CAS  Google Scholar 

  14. Bloedon LT, Jeffcoat AR, Lopaczynski W, Schell MJ, Black TM, Dix KJ, Thomas BF, Albright C, Busby MG, Crowell JA, Zeisel SH (2002) Safety and pharmacyokinetics of purifyied soy isoflavones: single-dose administration to postmenopausal women. Am J Clin Nutr 76(5):1126–1137

    Article  CAS  PubMed  Google Scholar 

  15. Sakuma K, Akiho M, Nakashima H, Nakao R, Hirata M, Inashima S, Yamaguchi A, Yasuhara M (2008) Cyclosporin A modulates cellular localization of MEF2C protein and blocks fiber hypertrophy in the overloaded soleus muscle of mice. Acta Neuropathol 115(6):663–674

    Article  CAS  PubMed  Google Scholar 

  16. Akiho M, Nakashima H, Sakata M, Yamasa Y, Yamaguchi A, Sakuma K (2010) Expression profile of Notch-1 in mechanically overloaded plantaris muscle of mice. Life Sci 86(1–2):59–65

    Article  CAS  PubMed  Google Scholar 

  17. Henriques A, Croixmarie V, Priestman DA, Rosenbohm A, Dirrig-Grosch S, D’Ambra E, Huebecker M, Hussain G, Boursier-Neyret C, Echaniz-Laguna A, Ludolph AC, Platt FM, Walther B, Spedding M, Loeffler JP, Gonzalez De Aguilar JL (2015) Amyotrophic lateral sclerosis and denervation alter sphingolipids and up-regulate glucosylceramide synthase. Hum Mol Genet 24(25):7390–7405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wall BT, Dirks ML, Snijders T, Stephens FB, Senden JM, Verscheijden ML, van Loon LJ (2015) Short-term muscle disuse atrophy is not associated with increased intramuscular lipid deposition or a decline in the maximal activity of key mitochondrial enzymes in young and older males. Exp Gerontol 61:76–83

    Article  CAS  PubMed  Google Scholar 

  19. Palacios-González B, Zarain-Herzberg A, Flores-Galicia I, Noriega LG, Alemán-Escondrillas G, Zarinan T, Ulloa-Aguirre A, Torres N, Tovar AR (2014) Genistein stimulates fatty acid oxidation in a leptin receptor-independent manner through the JAK2-mediated phosphorylation and activation of AMPK in skeletal muscle. Biochim Biophys Acta 1841(1):132–140

    Article  CAS  PubMed  Google Scholar 

  20. Wei JH, Chang NC, Chen SP, Geraldine P, Jayakumar T, Fong TH (2015) Comparative decline of the protein profiles of nebulin in response to denervation in skeletal muscle. Biochem Biophys Res Commun 466(1):95–102

    Article  CAS  PubMed  Google Scholar 

  21. MacDonald EM, Andres-Mateos E, Mejias R, Simmers JL, Mi R, Park JS, Ying S, Hoke A, Lee SJ, Cohn RD (2014) Denervation atrophy is independent from Akt and mTOR activation and is not rescued by myostatin inhibition. Dis Model Mech 7(4):471–481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Sandri M, Barberi L, Bijlsma AY, Blaauw B, Dyar KA, Milan G, Mammucari C, Meskers CG, Pallafacchina G, Paoli A, Pion D, Roceri M, Romanello V, Serrano AL, Toniolo L, Larsson L, Maier AB, Muñoz-Cánoves P, Musarò A, Pende M, Reggiani C, Rizzuto R, Schiaffino S (2013) Signaling pathways regulating muscle mass in ageing skeletal muscle. The role of IGF-1-Akt-mTOR-FoxO pathway. Biogerontology 14(3):303–323

    Article  CAS  PubMed  Google Scholar 

  23. Hwee DT, Baehr LM, Philp A, Baar K, Bodinne SC (2014) Maintenance of muscle mass and load-induced growth in muscle RING finger 1 null mice with age. Aging Cell 13(1):92–101

    Article  CAS  PubMed  Google Scholar 

  24. Bodine SC, Latres E, Baumhueter S, Lai VK-M, Nunez L, Clarke BA, Poueymirou WT, Panaro FJ, Na E, Dharmarajan K, Pan Z-Q, Valenzuela DM, DeChiara TM, Stitt TN, Yancopoulos GD, Glass DJ (2001) Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294(5547):1704–1708

    Article  CAS  Google Scholar 

  25. Bodine SC, Baehr LM (2014) Skeletal muscle atrophy and the E3 ubiquitin ligases MuRF1 and MAFbx/atrogin-1. Am J Physiol Endocrinol Metab 307(6):E469–E484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sun H, Qiu J, Chen Y, Yu M, Ding F, Gu X (2014) Proteomic and bioinformatic analysis of differentially expressed proteins in denervated skeletal muscle. Int J Mol Med 33(6):1586–1596

    Article  CAS  PubMed  Google Scholar 

  27. Alamdari N, Aversa Z, Castillero E, Gurav A, Petkova V, Tizio S, Hasselgren PO (2012) Resveratrol prevents dexamethasone-induced expression of the muscle atrophy-related ubiquitin ligases atrogin-1 and MuRF1 in cultured myotubes through a SIRT1-dependent mechanism. Biochem Biophys Res Commun 417(1):528–533

    Article  CAS  PubMed  Google Scholar 

  28. Sin TK, Yung BY, Yip SP, Chan LW, Wong CS, Tam EW, Siu PM (2015) SIRT1-dependent myoprotective effects of resveratrol on muscle injury induced by compression. Front Physiol 6:293

    Article  PubMed  PubMed Central  Google Scholar 

  29. Le NH, Kim CS, Park T, Park JH, Sung MK, Lee DG, Hong SM, Choe SY, Goto T, Kawada T, Yu R (2014) Quercetin protects against obesity-induced skeletal muscle inflammation and atrophy. Mediat Inflamm 2014:834294

    Article  CAS  Google Scholar 

  30. Siu PM, Always SE (2009) Response and adaptation of skeletal muscle to denervation stress: the role of apoptosis in muscle loss. Front Biosci 14:432–452

    Article  CAS  PubMed Central  Google Scholar 

  31. Siu PM, Always SE (2005) Mitochondria-associated apoptotic signalling in denervated rat skeletal muscle. J Physiol 565(Pt 1):309–323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hopkins D, Manchester KL, Gregory M (1983) Histochemical and biochemical characteristics of the transient hypertrophy of the denervated rat hemidiaphragm. Exp Neurol 81(2):279–293

    Article  CAS  PubMed  Google Scholar 

  33. Connor EA, McMahan UJ (1987) Cell accumulation in the junctional region of denervated muscle. J Cell Biol 104(1):109–120

    Article  CAS  PubMed  Google Scholar 

  34. Damarla M, Parniani AR, Johnston L (2014) Mitogen-activated protein kinase-activated protein kinase 2 mediates apoptosis during lung vascular permeability by regulating movement of cleaved caspase 3. Am J Respirat Cell Mol Biol 50(5):932–941

    Article  CAS  Google Scholar 

  35. Messina S, Bitto A, Vita GL, Aguennouz M, Irrera N, Licata N, Sframeli M, Bruschetta D, Minutoli L, Altavilla D, Vita G, Squadrito F (2015) Modulation of neuronal nitric oxide synthase and apoptosis by the isoflavone genistein in mdx mice. Biofactors 41(5):324–329

    Article  CAS  PubMed  Google Scholar 

  36. Cea LA, Cisterna BA, Puebla C, Frank M, Figueroa XF, Cardozo C, Willecke K, Latorre R, Sáez JC (2013) De novo expression of connexin hemichannels in denervated fast skeletal muscles leads to atrophy. Proc Natl Acad Sci USA 110(40):16229–16234

    Article  PubMed  Google Scholar 

Download references


This work was supported by a research Grant-in-Aid for Scientific Research C (No. 17K01755) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Kunihiro Sakuma.

Ethics declarations

Conflict of interest

Kunihiro Sakuma and all the co-authors declare that they have no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tabata, S., Aizawa, M., Kinoshita, M. et al. The influence of isoflavone for denervation-induced muscle atrophy. Eur J Nutr 58, 291–300 (2019).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • Isoflavone
  • Muscle atrophy
  • Supplementation
  • Atrogin-1
  • Apoptosis
  • Denervation