The expression of aquaporin-4 is regulated based on innervation in skeletal muscles

  • Minenori IshidoEmail author
  • Tomohiro Nakamura


Aquaporin-4 (AQP4) is a selective water channel, which expresses on the plasma membrane of myofibers and regulates the osmotic pressure, energy metabolism and morphological changes in myofibers by modulating water transport across sarcolemma in skeletal muscles. Although the physiological roles of AQP4 have been gradually clarified in skeletal muscles, the regulatory mechanisms of AQP4 expression have been poorly understood in skeletal muscles. Recently, it was reported that the expression of AQP4 decreased in atrophied skeletal muscles following sciatic nerve transection, but not tail-suspension. Therefore, expecting that the nerve supply to myofibers would be one of the major regulatory factors regulating AQP4 expression in skeletal muscles, we investigated whether the expression patterns of AQP4 were changed in skeletal muscles by denervation and subsequent reinnervation. As a result, while the APQ4 expression levels were significantly decreased by sciatic nerve freezing-induced denervation, subsequently the expression levels of AQP4 were fully restored during reinnervation in skeletal muscles (p < 0.05, respectively). On the other hand, the expression levels of α1-syntrophin and AQP1, which are respectively structural and functional related AQP4 factors, were stably maintained during the denervation and subsequent reinnervation. Therefore, the present study demonstrated that the expression of AQP4 may be regulated depending on the innervation to skeletal muscles. Moreover, AQP4 regulatory mechanisms may be fundamentally different to those of AQP1 in skeletal muscles.


Skeletal muscle Denervation AQP4 Reinnervation 



This study was supported by a Grant-in Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (JSPS KAKENHI Grant Number JP17K01771).

Compliance with ethical standards

Conflict of interest

All authors declare no conflicts of interest.


  1. Adams ME, Mueller HA, Froehner SC (2001) In vivo requirement of the alpha-syntrophin PDZ domain for the sarcolemmal localization of nNOS and aquaporin-4. J Cell Biol 155:113–122CrossRefPubMedPubMedCentralGoogle Scholar
  2. Au CG, Cooper ST, Lo HP, Compton AG, Yang N, Wintour EM, North KN, Winlaw DS (2004) Expression of aquaporin 1 in human cardiac and skeletal muscle. J Mol Cell Cardiol 36:655–662CrossRefGoogle Scholar
  3. Au CG, Butler TL, Egan JR, Cooper ST, Lo HP, Compton AG, North KN, Winlaw DS (2008) Changes in skeletal muscle expression of AQP1 and AQP4 in dystrophinopathy and dysferlinopathy patients. Acta Neuropathol 116:235–246CrossRefGoogle Scholar
  4. Basco D, Nicchia GP, D’Alessandro A, Zolla L, Svelto M, Frigeri A (2011) Absence of aquaporin-4 in skeletal muscle alters proteins involved in bioenergetic pathways and calcium handling. PLoS One 6:e19225CrossRefPubMedPubMedCentralGoogle Scholar
  5. Basco D, Blaauw B, Pisani F, Sparaneo A, Nicchia GP, Mola MG, Reggiani C, Svelto M, Frigeri A (2013) AQP4-dependent water transport plays a functional role in exercise-induced skeletal muscle adaptations. PLoS One 8:e58712CrossRefPubMedPubMedCentralGoogle Scholar
  6. Bodine SC, Latres E, Baumhueter S, Lai VK, Nunez L, Clarke BA, Poueymirou WT, Panaro FJ, Na E, Dharmarajan K, Pan ZQ, Valenzuela DM, DeChiara TM, Stitt TN, Yancopoulos GD, Glass DJ (2001) Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294:1704–1708CrossRefGoogle Scholar
  7. Calderon JC, Bolanos P, Caputo C (2014) The excitation-contraction coupling mechanism in skeletal muscle. Biophys Rev 6:133–160CrossRefPubMedPubMedCentralGoogle Scholar
  8. Crosbie RH, Dovico SA, Flanagan JD, Chamberlain JS, Ownby CL, Campbell KP (2002) Characterization of aquaporin-4 in muscle and muscular dystrophy. FASEB J 16:943–949CrossRefGoogle Scholar
  9. Frigeri A, Nicchia GP, Verbavatz JM, Valenti G, Svelto M (1998) Expression of aquaporin-4 in fast-twitch fibers of mammalian skeletal muscle. J Clin Invest 102:695–703CrossRefPubMedPubMedCentralGoogle Scholar
  10. Frigeri A, Nicchia GP, Desaphy JF, Pierno S, De Luca A, Camerino DC, Svelto M (2001a) Muscle loading modulates aquaporin-4 expression in skeletal muscle. FASEB J 15:1282–1284CrossRefGoogle Scholar
  11. Frigeri A, Nicchia GP, Nico B, Quondamatteo F, Herken R, Roncali L, Svelto M (2001b) Aquaporin-4 deficiency in skeletal muscle and brain of dystrophic mdx mice. FASEB J 15:90–98CrossRefGoogle Scholar
  12. Frigeri A, Nicchia GP, Balena R, Nico B, Svelto M (2004) Aquaporins in skeletal muscle: reassessment of the functional role of aquaporin-4. FASEB J 18:905–907CrossRefGoogle Scholar
  13. Gomes MD, Lecker SH, Jagoe RT, Navon A, Goldberg AL (2001) Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy. Proc Natl Acad Sci USA 98:14440–14445CrossRefGoogle Scholar
  14. Grant AC, Gow IF, Zammit VA, Shennan DB (2000) Regulation of protein synthesis in lactating rat mammary tissue by cell volume. Biochim Biophys Acta 1475:39–46CrossRefGoogle Scholar
  15. Hara H, Wakayama Y, Kojima H, Inoue M, Jimi T, Iijima S, Masaki H (2011) Aquaporin 4 expression in the mdx mouse diaphragm. Acta Histochem Cytochem 44:175–182CrossRefPubMedPubMedCentralGoogle Scholar
  16. Hudlicka O (2011) Microcirculation in skeletal muscle. Muscles Ligaments Tendons J 1:3–11PubMedPubMedCentralGoogle Scholar
  17. Hyatt JP, Roy RR (2003) Nerve activity-independent regulation of skeletal muscle atrophy: role of MyoD and Myogenin in satellite cells and myonuclei. Am J Physiol Cell Physiol 285:C1161–73CrossRefGoogle Scholar
  18. Ichinose E, Kurose T, Daitoku D, Kawamata S (2008) The skeletal muscle vascular supply closely correlates with the muscle fiber surface area in the rat. Arch Histol Cytol 71:45–57CrossRefGoogle Scholar
  19. Ishido M, Nakamura T (2016) Aquaporin-4 protein is stably maintained in the hypertrophied muscles by functional overload. Acta Histochem Cytochem 49:89–95CrossRefPubMedPubMedCentralGoogle Scholar
  20. Ishido M, Nakamura T (2017) Marked decrease of aquaporin-4 protein is independent of the changes in alpha1-syntrophin and TRPV4 levels in response to denervation-induced muscle atrophy in vivo. J Muscle Res Cell Motil 38:175–181CrossRefGoogle Scholar
  21. Jimi T, Wakayama Y, Murahashi M, Shibuya S, Inoue M, Hara H, Matsuzaki Y, Uemura N (2000) Aquaporin 4: lack of mRNA expression in the rat regenerating muscle fiber under denervation. Neurosci Lett 291:93–96CrossRefGoogle Scholar
  22. Jimi T, Wakayama Y, Inoue M, Kojima H, Oniki H, Matsuzaki Y, Shibuya S, Hara H, Takahashi J (2006) Aquaporin 1: examination of its expression and localization in normal human skeletal muscle tissue. Cells Tissues Organs 184:181–187CrossRefGoogle Scholar
  23. Kozono D, Yasui M, King LS, Agre P (2002) Aquaporin water channels: atomic structure molecular dynamics meet clinical medicine. J Clin Invest 109:1395–1399CrossRefPubMedPubMedCentralGoogle Scholar
  24. Low SY, Rennie MJ, Taylor PM (1997) Signaling elements involved in amino acid transport responses to altered muscle cell volume. FASEB J 11:1111–1117CrossRefGoogle Scholar
  25. Mendler L, Pintér S, Kiricsi M, Baka Z, Dux L (2008) Regeneration of reinnervated rat soleus muscle is accompanied by fiber transition toward a faster phenotype. J Histochem Cytochem 56:111–123CrossRefPubMedPubMedCentralGoogle Scholar
  26. Millar ID, Barber MC, Lomax MA, Travers MT, Shennan DB (1997) Mammary protein synthesis is acutely regulated by the cellular hydration state. Biochem Biophys Res Commun 230:351–355CrossRefGoogle Scholar
  27. Neely JD, Amiry-Moghaddam M, Ottersen OP, Froehner SC, Agre P, Adams ME (2001) Syntrophin-dependent expression and localization of Aquaporin-4 water channel protein. Proc Natl Acad Sci USA 98:14108–14113CrossRefGoogle Scholar
  28. Neering IR, Quesenberry LA, Morris VA, Taylor SR (1991) Nonuniform volume changes during muscle contraction. Biophys J 59:926–933CrossRefPubMedPubMedCentralGoogle Scholar
  29. Nicchia GP, Mola MG, Pisoni M, Frigeri A, Svelto M (2007) Different pattern of aquaporin-4 expression in extensor digitorum longus and soleus during early development. Muscle Nerve 35:625–631CrossRefGoogle Scholar
  30. Nishizawa T, Yamashia S, McGrath KF, Tamaki H, Kasuga N, Takekura H (2006) Plasticity of neuromuscular junction architectures in rat slow and fast muscle fibers following temporary denervation and reinnervation processes. J Muscle Res Cell Motil 27:607–615CrossRefGoogle Scholar
  31. Pirkmajer S, Chibalin AV (2016) Na,K-ATPase regulation in skeletal muscle. Am J Physiol Endocrinol Metab 311:E1–E31CrossRefGoogle Scholar
  32. Preston GM, Agre P (1991) Isolation of the cDNA for erythrocyte integral membrane protein of 28 kilodaltons: member of an ancient channel family. Proc Natl Acad Sci USA 88:11110–11114CrossRefGoogle Scholar
  33. Preston GM, Carroll TP, Guggino WB, Agre P (1992) Appearance of water channels in Xenopus oocytes expressing red cell CHIP28 protein. Science 256:385–387CrossRefGoogle Scholar
  34. Sakakima H, Kawamata S, Kai S, Ozawa J, Matsuura N (2000) Effects of short-term denervation and subsequent reinnervation on motor endplates and the soleus muscle in the rat. Arch Histol Cytol 63:495–506CrossRefGoogle Scholar
  35. Schulte L, Peters D (1994) Sarcoplasmic reticulum Ca2+ pump expression in denervated skeletal muscle. Am J Physiol 267:C617–C622CrossRefGoogle Scholar
  36. Stoll B, Gerok W, Lang F, Häussinger D (1992) Liver cell volume and protein synthesis. Biochem J 287:217–222CrossRefPubMedPubMedCentralGoogle Scholar
  37. Takekura H, Tamaki H, Nishizawa T, Kasuga N (2003) Plasticity of the transverse tubules following denervation and subsequent reinnervation in rat slow and fast muscle fibres. J Muscle Res Cell Motil 24:439–451CrossRefGoogle Scholar
  38. Wagatsuma A, Osawa T (2006) Time course of changes in angiogenesis-related factors in denervated muscle. Acta Physiol (Oxf) 187:503–509CrossRefGoogle Scholar
  39. Wagatsuma A, Tamaki H, Ogita F (2005) Capillary supply and gene expression of angiogenesis-related factors in murine skeletal muscle following denervation. Exp Physiol 90:403–409CrossRefPubMedPubMedCentralGoogle Scholar
  40. Wakayama Y, Jimi T, Inoue M, Kojima H, Murahashi M, Kumagai T, Yamashita S, Hara H, Shibuya S (2002) Reduced aquaporin 4 expression in the muscle plasma membrane of patients with Duchenne muscular dystrophy. Arch Neurol 59:431–437CrossRefGoogle Scholar
  41. Yang B, Verkman AS (1997) Water and glycerol permeabilities of aquaporins 1–5 and MIP determined quantitatively by expression of epitope-tagged constructs in Xenopus oocytes. J Biol Chem 272:16140–16146CrossRefGoogle Scholar
  42. Yokota T, Miyagoe Y, Hosaka Y, Tsukita K, Kameya S, Shibuya S, Matsuda R, Wakayama Y, Takeda S (2000) Aquaporin-4 is absent at the sarcolemma and at perivascular astrocyte endfeet in α1-syntrophin knockout mice. Proc Japan Acad 76:22–27CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Section for Health-related Physical Education, Division of Human Sciences, Faculty of EngineeringOsaka Institute of TechnologyOsakaJapan

Personalised recommendations