Hearing loss is the most common form of sensory impairment in humans, affecting over 7% of the world’s population (466 million people) according to WHO (WHO, 2018). This impairing disability is caused by genetic defects, environmental factors or a combination of both. Genetic hearing loss, including non-syndromic and syndromic deafness, is estimated to account for 50% of cases. Certain mutations can also cause susceptibility to noise-induced damage, presbycusis and other complex forms of hearing loss (Shearer et al., 1993).

Clinical heterogeneity reflects the rich cellular and molecular complexity of the cochlea. Indeed the development of the inner ear and the maintenance of hearing throughout life requires the precise spatial and temporal expression of a variety of genes, as well as the strict regulation of the interactome (Hickox et al., 2017; Liu et al., 2014; Shearer et al., 1993). The phenotypic and genetic heterogeneity of hearing loss is still under study, and to this end animal studies and particularly mice model systems are fundamental tools (Bowl et al., 2017). Their characterization will help us to develop new therapeutic strategies and to understand the molecular relationship between environmental and genetic factors in the establishment of the different types of sensorineural hearing loss.

Age-related hearing loss (ARHL) is a form of progressive hearing loss and a degenerative process. ARHL arises due to impaired function and consequent cellular loss, both in the peripheral inner ear structures and in central elements of the auditory pathway (Lee, 2013). It is thought to be multifactorial and the result of poorly understood genetic susceptibility and environmental factors, such as exposure to excessive noise, ototoxic chemicals, and medical conditions that exacerbate hearing loss in older people (Joo et al., 2016).

Studies in humans and animal models, particularly mice, have pointed to oxidative stress and mitochondrial dysfunction as hallmarks of ageing in several tissues (López-Otín et al., 2013), including the cochlea (Müller and Barr-Gillespie, 2015; Ren et al., 2013; Uchida et al., 2011).

Mitogen-activated protein kinases (MAPKs) are intracellular protein Ser/Thr kinases that, upon phosphorylation in response to extracellular stimuli, regulate cellular responses such as proliferation, differentiation, motility and survival. The classical MAPKs include ERK1/2/5, which induce tissue growth and survival, and the stress-activated protein kinases JNK1/2/3 and p38 isoforms (MAPK11/12/13/14), which are mediators of several stress stimuli (Cargnello and Roux, 2011; Gupta and Nebreda, 2015; Kyriakis and Avruch, 2012).

JNK and p38 MAPK transcripts and proteins are expressed in the cochlea from late intrauterine development (Parker et al., 2015; Sanchez-Calderon et al., 2010). They form part of the adult cochlear response to noise insult (Jamesdaniel et al., 2011; Maeda et al., 2013) and to ageing (Sha et al., 2009). In this connection, their chemical inhibition promotes the survival of cochlear cells after damage (Tabuchi et al., 2010; Wang et al., 2007).

MAP kinase phosphatases (MKP) belong to the large family of dual-specificity phosphatases. These proteins contain a conserved kinase-interaction motif and specifically dephosphorylate the threonine and tyrosine residues of phosphorylated activated MAPKs, thereby controling the duration, magnitude and spatiotemporal profile of their activities (Owens and Keyse, 2007).

MKPs can be subdivided into three classes on the basis of their gene structure, sequence similarity and subcellular localization. The first is formed by inducible nuclear phosphatases and includes MKP1 (DUSP1), PAC1 (DUSP2), MKP2 (DUSP4) and HVH3 or DUSP5, which target all classic MAPK with different substrate affinities. The second class includes the cytoplasmic phosphatases MKP3 (DUSP6), MKPX (DUSP7) and MKP4 (DUSP9), which preferentially inactivate ERK1/ERK2. The third class comprises DUSP8, MKP5 (DUSP10) and MKP7 (DUSP16), which can be both nuclear and cytoplasmic and which target stress-activated MAPKs isoforms (Owens and Keyse, 2007). Among the first class, DUSP1 is an inducible and primarily nuclear phosphatase that is the principal regulator of the stress MAPKs (Franklin and Kraft, 1997).

MKPs are involved in immune cell function, regulating the inflammatory responses both positively and negatively depending on the specific MKP (Huang and Tan, 2012). Their dysregulation has also been associated with different types of cancer and pace of cancer progression (Bermudez et al., 2010).

Here, we describe the auditory phenotype of the Dusp1 null mouse. Our results show that: (i) DUSP1 is expressed in the mouse cochlea with a temporal age-regulated pattern; (ii) DUSP1 deficit leads to a premature onset of hearing loss and to an accelerated progression of the hearing-loss phenotype that is caused by the degeneration and death of the sensory epithelium and spiral ganglion neurons in the cochlea; and (iii) dysregulated oxidative balance and exacerbated inflammatory response are among the mechanisms underlying hearing loss in Dusp1-deficient mice.

In this work, we show that Dusp1 plays a key role in hearing maintenance and, therefore, its deficit accelerates progressive hearing loss as mice age. DUSP1-deficient mice show progressive hearing loss with age, and cochlear cellular degeneration progresses with age from the cochlear base to the apex.

DUSP1 has been classified as an inducible nuclear phosphatase but it has also been found in cytosol, mitochondria and peroxisomes (Kataya et al., 2015). This protein dephosphorylates MAPK proteins, with substrate specificity for p38 and JNK (Patterson et al., 2009). DUSP1 is an early-response gene that is induced transitorily by different stress-related stimuli (Gass et al., 1996). DUSP1 expression is low during development in almost all tissues except liver and intestine. RNAseq studies indicate that it is expressed in the cochlea and vestibule, particularly in supporting cells (data available from gEAR, umgear.org) (Burns et al., 2015; Elkon et al., 2015; Liu et al., 2014; Scheffer et al., 2015), and that it is upregulated in the cochlea after exposure to noise (Alagramam et al., 2014). In general, MKP family members have been reported to present low basal levels of expression in most tissues (Camps et al., 2000) but they are rapidly induced after stress stimuli. Accordingly, we have observed here that DUSP1 expression is induced in Dusp1^+/+ MEF by 30 min of UV irradiation and in Dusp1^+/+ cochlea by 30 min of exposure to noise.

The MKP family includes many members that have broad substrate specificity. Studies using MKP-deficient in vivo models have shown that the deletion of one family member typically results in a complex phenotype, which reflects the complex transcriptional regulation of these proteins by MAP kinases and the compensatory effects of other MKPs (Huang and Tan, 2012). In this work, we have observed that Dusp1 transcripts show their highest expression levels in the cochlea among the nuclear-inducible MKPs, and interestingly that these expression levels increase with age. These data suggest that an increase in DUSP1 expression level is required to maintain hearing with age. Other family members do not seem to compensate for the specific action of DUSP1 in the cochlea, although they could potentially contribute to ameliorating the hearing phenotype through the increased expression of Dusp2. DUSP2 is a nuclear phosphatase, enriched in hematopoietic cells, that is specific for ERK and p38. It is a positive regulator of inflammatory response, and so the macrophages of Dusp2 null mice produce lower levels of pro-inflammatory cytokines. This deficit is accompanied by the decreased and increased activation of ERK and JNK, respectively (Owens and Keyse, 2007). However, as none of the MKPs studied here showed expression changes as the mice aged, it seems that there are no alternative compensatory mechanisms to DUSP1 protection in age-related hearing loss.

MKP family members Dusp6, Dusp7 and Dusp9, which mainly target ERK1/2, have been reported to be expressed during inner ear development (Urness et al., 2008). Indeed, the inactivation of Dusp6 leads to hypoacusis that results from malformations in the middle ear and otic capsule but not in the cochlea (Li et al., 2007). By contrast, we show here that DUSP1 deficit does not affect either middle ear or otic capsule formation. Indeed, the hearing-loss phenotype of the null mice has a clear correlation with the progressive loss of cochlear cell populations, particularly the loss of the hair and supporting cells of the organ of Corti and of the neural cells of the spiral ganglion. Reported human ARHL cochlear alterations include changes to structural elements such as hair cells, neurons, lateral wall tissues, or a combination thereof (Kusunoki et al., 2004; Nelson and Hinojosa, 2006). Thus, the cochlear phenotype of the Dusp1 null mouse reproduces that reported for human ARHL, and shares characteristics with other animal models of progressive hearing loss (Dubno et al., 2013; Espino Guarch et al., 2018; Riquelme et al., 2010), including increased apoptotic cell death in the ageing cochlea (Sha et al., 2009).

Our data suggest that the activity of DUSP1 is an essential piece of the molecular mechanism involved in otoprotection during ageing. Indeed, DUSP1 has already been described as neuroprotective (Collins et al., 2013; Taylor et al., 2013) and as a regulator of neuroinflammatory processes (Collins et al., 2015). Low levels of DUSP1 have been associated with neurological pathologies such as Huntington disease, multiple sclerosis, ischemia or cerebral hypoxia (Collins et al., 2015). Interestingly, BDNF-induced axon branching is regulated by DUSP1 during development (Jeanneteau et al., 2010; Mullen et al., 2012). Although 2-month-old null mice already have worse hearing thresholds than their wildtype littermates, we did not observe a gross cochlear developmental defect. Nevertheless, these young mice already show defective temporal processing and responsiveness of auditory signal. As in other murine models of ARHL, at later ages this defect is not compensated for in the central stations of the auditory pathway (Möhrle et al., 2016). These differences were not observed in one-month-old null mice, suggesting that young null mice have subtle hearing deficiencies that are most possibly related to alterations in basic molecular mechanisms.

The increased production of ROS found in H₂O₂-stimulated MEF from embryonic null mice supports this concept, and points to chronic oxidative stress as one of the possible causes of later problems. This redox imbalance was further confirmed in the cochlea of young null mice by the detection of 3-NT, a metabolite of peroxynitrite action that is increased in the ageing ear (Jiang et al., 2007). Indeed, abnormally increased ROS levels play a role in ageing and in the onset and progression of age-related diseases (Balaban et al., 2005), including presbycusis (Yang et al., 2015). Mitochondria are the source of 90% of intracellular ROS, which are a byproduct of mitochondrial respiration, and one of the main targets of the oxidative damage caused by them. ROS can also be generated by non-mitochondrial sources such as the NADPH oxidases (Di Meo et al., 2016). DUSP1 upregulation is induced by ROS, specifically by those produced by NADPH oxidases (Fürst et al., 2005), and the transitory expression of this protein can also be stabilized by RNA-binding proteins in contexts of oxidative stress (Kuwano et al., 2008). Interestingly, the observed cochlear cell loss follows a gradient from base to apex. It is well known that basal structures are more susceptible in general to insult (Murillo-Cuesta et al., 2010; Sanz et al., 2015; Takada et al., 2014) and in particular to ageing (Makary et al., 2011; Nadol, 1979; Ohlemiller et al., 2010). It has been proposed that higher basal susceptibility to damage is the result of increased ROS generation (Choung et al., 2009) and that basal hair cells are highly damaged by free oxygen radicals (Sha et al., 2001).

Dusp1 null mice present an early decrease of mitochondrial uncoupling protein 1 (UCP1), as well as an imbalance of NAPDH oxidases. Uncoupling proteins facilitate the dissipation of the proton gradient needed for oxidative phosphorylation, leading to heat generation and reduced ROS generation by mitochondria (Kazak et al., 2017). UCP1–UCP5 are expressed in the spiral and vestibular ganglia and are upregulated by some stress stimuli (Kitahara et al., 2005; Rodríguez-de la Rosa et al., 2015). On the other hand, the NADPH oxidase NOX3 constitutively generates superoxide, which is further converted to H₂O₂, in a p22PHOX-dependent manner. NOX3 is expressed in the vestibular and cochlear sensory epithelium and spiral ganglion (Bánfi et al., 2004). NOX3 is downregulated by noise (Vlajkovic et al., 2013) and participates in cisplatin-induced superoxide formation and ototoxicity (Kaur et al., 2016). Protection from ROS-induced damage is achieved by a complex system of antioxidant enzymes: superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and peroxiredoxin (Poirrier et al., 2010). It has been proposed that, with ageing, the imbalance between increased production and impaired detoxification systems leads to a pro-oxidative state (Nóbrega-Pereira et al., 2016). Thus, natural ageing could lead to oxidative damage to hair cells and ganglion neurons, which require great amounts of energy to process sound, ultimately leading to cell and functional loss (Miller, 2015).

In fact, oxidative stress and mitochondrial dysfunction are the underlying mechanisms pointed to by many of the uncovered genetic factors associated with ARHL. For example, genetically modified mice that have defects affecting Gpx1, Sod1, Polg1, mt-Tr, and Cs show traits of ARHL (Bowl and Dawson, 2015; Müller and Barr-Gillespie, 2015). Human genetic studies of ARHL have also identified polymorphisms of genes in the same functional category, such as CAT, MTHFR, MTR, and UCP2, within a single cohort (Dawes and Payton, 2016). The glutathione-transferase genes (GSTM1 and GSTT1) (Bared et al., 2010; Van Eyken et al., 2007) and N-Acetyltransferase 2 (NAT2) have also been studied extensively and associated with human ARHL (Unal et al., 2005; Van Eyken et al., 2007). Dusp1 null mice present an early imbalance in ROS-detoxifying enzymes (MnSOD) and in glutathione synthesis (Glcm) and metabolism (Gpx1 and Gsr) enzymes. A functional imbalance is implied because levels of mRNAs encoding antioxidant enzymes have been shown to correlate with protein levels and enzyme activities (Iskusnykh et al., 2013; Sikalidis et al., 2014; Takeshita et al., 2000). Ageing is associated with increasing oxidation, the progression of cellular damage and cell death, but here, levels mRNAs that encode redox enzymes are altered only in 2-month-old null mice. This situation could be similar to that reported in apolipoprotein E (APOE)-deficient mice, in which a pre-lesion increase in antioxidant enzymes is followed by a decrease once the vascular lesion is extended (Hoen et al., 2003).

Taken together, these results suggest the existence of a pro-oxidative stage predisposition in the DUSP1-deficient mouse. Our data point to the activation of MAPK14 as the possible link between the absence of DUSP1 and a premature increase in cochlear oxidative stress and pro-inflammatory status. MAPK14 is expressed in the cochlea (Parker et al., 2015; Sanchez-Calderon et al., 2010) and it is activated at different time points after noise insult (Jamesdaniel et al., 2011; Maeda et al., 2013; Murillo-Cuesta et al., 2015), as well as during ageing (Sha et al., 2009). We show here that DUSP1 is induced by noise-exposure and that its transcription increases with age. MAPK14 inhibitors attenuate mitochondrial and cytoplasmic ROS production in DUSP1-deficient macrophages (Talwar et al., 2017). In this sense, the suppression of MAPK14 activity has been linked with protection from mitochondrial dysfunction and ROS generation in different pathologies (Huang et al., 2018; Yu et al., 2017). Furthermore, the inhibition of MAPK14 downregulates the expression of NADPH oxidase, whereas the activation of MAPK14 induces the phosphorylation and activation of NADPH oxidase subcomponents, potentially leading to enhanced ROS production (Manea et al., 2015). These previous sources of evidence are in agreement with our results: Dusp1 null mice exhibited increased sensitivity to noise exposure, whereas Mapk14^KI/KI mice showed better hearing thresholds and better auditory recovery after the insult than wildtype mice, suggesting an important role of MAPK14/DUSP1 in the progression of stress-induced injury.

Dusp1 deficiency also leads to an early increase in kidney injury molecule-1 (KIM-1), which is induced in the cochlea after cisplatin treatment (Mukherjea et al., 2006) and is involved in kidney inflammatory processes that regulate macrophage activation and migration (Tian et al., 2017). Chronic inflammation has been associated with the worsening of human presbycusis (Verschuur et al., 2014). NOX3-produced ROS is coupled with the production of inflammatory cytokines (Mukherjea et al., 2011) and DUSP1 is an important regulator of the innate immune responses (Chi et al., 2006). A chronic inflammatory state that occurs as a consequence of ageing of the immune system (known as ‘inflammaging’) is another hallmark of cochlear ageing (Kalinec et al., 2017). In this context, Dusp1 null mice present an exacerbated inflammatory response from the age of 5 months onwards. Our results suggest that an inflammatory feedback loop may exist in which the presence of inflammatory cytokines, the absence of DUSP1 and the consequent activation of stress kinases enhances cellular apoptosis.

Null mice showed increased expression of cytokines and of IBA1-positive phagocytic cells from the youngest age studied. Interestingly, during normal ageing, resident macrophages increase in number and undergo changes in morphology that are directly associated with the degeneration of sensorial cells (Frye et al., 2017). Chronic inflammation causes damage to cells that are quickly removed from the cochlea (Hu et al., 2002). Resident macrophages and supporting cells of the organ of Corti have been proposed as the effectors of the cleaning of cellular debris (Anttonen et al., 2014; Hirose et al., 2005).

Taken together, our results show that Dusp1 deficiency accelerates the onset and the progression of age-related hearing loss. Our results therefore suggest that DUSP1 is essential for lifelong cochlear homeostasis.

Source data files have been provided for ABR data in Figures 2 and Figure2-figure supplement 1, as well as for gene expression data in Figures 1, 3, 5, 6 and Figure1-figure supplement 1. Data has also been deposited on Dryad under the doi: 10.5061/dryad.51m8c58.

1. 1. Celaya AM
   2. Sánchez-Pérez I

   (2019) Dryad Digital Repository

   Data from: Deficit of mitogen-activated protein kinase phosphatase 1 (MKP1) accelerates progressive hearing loss.

   https://doi.org/10.5061/dryad.51m8c58

1. 1. Alagramam KN
   2. Stepanyan R
   3. Jamesdaniel S
   4. Chen DH
   5. Davis RR

   (2014) Noise exposure immediately activates cochlear mitogen-activated protein kinase signaling

   Noise and Health 16:400–409.

   https://doi.org/10.4103/1463-1741.144418

   • PubMed
   • Google Scholar
2. 1. Anttonen T
   2. Belevich I
   3. Kirjavainen A
   4. Laos M
   5. Brakebusch C
   6. Jokitalo E
   7. Pirvola U

   (2014) How to bury the dead: elimination of apoptotic hair cells from the hearing organ of the mouse

   Journal of the Association for Research in Otolaryngology 15:975–992.

   https://doi.org/10.1007/s10162-014-0480-x

   • PubMed
   • Google Scholar
3. 1. Balaban RS
   2. Nemoto S
   3. Finkel T

   (2005) Mitochondria, oxidants, and aging

   Cell 120:483–495.

   https://doi.org/10.1016/j.cell.2005.02.001

   • PubMed
   • Google Scholar
4. 1. Bánfi B
   2. Malgrange B
   3. Knisz J
   4. Steger K
   5. Dubois-Dauphin M
   6. Krause K-H

   (2004) NOX3, a Superoxide-generating NADPH Oxidase of the Inner Ear

   Journal of Biological Chemistry 279:46065–46072.

   https://doi.org/10.1074/jbc.M403046200

   • Google Scholar
5. 1. Bared A
   2. Ouyang X
   3. Angeli S
   4. Du LL
   5. Hoang K
   6. Yan D
   7. Liu XZ

   (2010) Antioxidant enzymes, presbycusis, and ethnic variability

   Otolaryngology–Head and Neck Surgery 143:263–268.

   https://doi.org/10.1016/j.otohns.2010.03.024

   • Google Scholar
6. 1. Bermudez O
   2. Pagès G
   3. Gimond C

   (2010) The dual-specificity MAP kinase phosphatases: critical roles in development and cancer

   American Journal of Physiology-Cell Physiology 299:C189–C202.

   https://doi.org/10.1152/ajpcell.00347.2009

   • PubMed
   • Google Scholar
7. 1. Bowl MR
   2. Simon MM
   3. Ingham NJ
   4. Greenaway S
   5. Santos L
   6. Cater H
   7. Taylor S
   8. Mason J
   9. Kurbatova N
   10. Pearson S
   11. Bower LR
   12. Clary DA
   13. Meziane H
   14. Reilly P
   15. Minowa O
   16. Kelsey L
   17. Tocchini-Valentini GP
   18. Gao X
   19. Bradley A
   20. Skarnes WC
   21. Moore M
   22. Beaudet AL
   23. Justice MJ
   24. Seavitt J
   25. Dickinson ME
   26. Wurst W
   27. de Angelis MH
   28. Herault Y
   29. Wakana S
   30. Nutter LMJ
   31. Flenniken AM
   32. McKerlie C
   33. Murray SA
   34. Svenson KL
   35. Braun RE
   36. West DB
   37. Lloyd KCK
   38. Adams DJ
   39. White J
   40. Karp N
   41. Flicek P
   42. Smedley D
   43. Meehan TF
   44. Parkinson HE
   45. Teboul LM
   46. Wells S
   47. Steel KP
   48. Mallon AM
   49. Brown SDM
   50. International Mouse Phenotyping Consortium

   (2017) A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

   Nature Communications 8:886.

   https://doi.org/10.1038/s41467-017-00595-4

   • PubMed
   • Google Scholar
8. 1. Bowl MR
   2. Dawson SJ

   (2015) The mouse as a model for age-related hearing loss - a mini-review

   Gerontology 61:149–157.

   https://doi.org/10.1159/000368399

   • PubMed
   • Google Scholar
9. 1. Burns JC
   2. Kelly MC
   3. Hoa M
   4. Morell RJ
   5. Kelley MW

   (2015) Single-cell RNA-Seq resolves cellular complexity in sensory organs from the neonatal inner ear

   Nature Communications 6:8557.

   https://doi.org/10.1038/ncomms9557

   • PubMed
   • Google Scholar
10. 1. Camarero G
    2. Avendano C
    3. Fernandez-Moreno C
    4. Villar A
    5. Contreras J
    6. de Pablo F
    7. Pichel JG
    8. Varela-Nieto I

    (2001) Delayed inner ear maturation and neuronal loss in postnatal Igf-1-deficient mice

    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 21:7630–7641.

    https://doi.org/10.1523/jneurosci.21-19-07630.2001

    • PubMed
    • Google Scholar
11. 1. Camps M
    2. Nichols A
    3. Arkinstall S

    (2000) Dual specificity phosphatases: a gene family for control of MAP kinase function

    The FASEB Journal 14:6–16.

    https://doi.org/10.1096/fasebj.14.1.6

    • PubMed
    • Google Scholar
12. 1. Cargnello M
    2. Roux PP

    (2011) Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases

    Microbiology and Molecular Biology Reviews 75:50–83.

    https://doi.org/10.1128/MMBR.00031-10

    • PubMed
    • Google Scholar
13. 1. Cediel R
    2. Riquelme R
    3. Contreras J
    4. Díaz A
    5. Varela-Nieto I

    (2006) Sensorineural hearing loss in insulin-like growth factor I-null mice: a new model of human deafness

    European Journal of Neuroscience 23:587–590.

    https://doi.org/10.1111/j.1460-9568.2005.04584.x

    • PubMed
    • Google Scholar
14. 1. Chi H
    2. Barry SP
    3. Roth RJ
    4. Wu JJ
    5. Jones EA
    6. Bennett AM
    7. Flavell RA

    (2006) Dynamic regulation of pro- and anti-inflammatory cytokines by MAPK phosphatase 1 (MKP-1) in innate immune responses

    PNAS 103:2274–2279.

    https://doi.org/10.1073/pnas.0510965103

    • PubMed
    • Google Scholar
15. 1. Choung YH
    2. Taura A
    3. Pak K
    4. Choi SJ
    5. Masuda M
    6. Ryan AF

    (2009) Generation of highly-reactive oxygen species is closely related to hair cell damage in rat organ of Corti treated with gentamicin

    Neuroscience 161:214–226.

    https://doi.org/10.1016/j.neuroscience.2009.02.085

    • PubMed
    • Google Scholar
16. 1. Collins LM
    2. O'Keeffe GW
    3. Long-Smith CM
    4. Wyatt SL
    5. Sullivan AM
    6. Toulouse A
    7. Nolan YM

    (2013) Mitogen-activated protein kinase phosphatase (MKP)-1 as a neuroprotective agent: promotion of the morphological development of midbrain dopaminergic neurons

    NeuroMolecular Medicine 15:435–446.

    https://doi.org/10.1007/s12017-013-8230-5

    • PubMed
    • Google Scholar
17. 1. Collins LM
    2. Downer EJ
    3. Toulouse A
    4. Nolan YM

    (2015) Mitogen-Activated protein kinase phosphatase (MKP)-1 in nervous system development and disease

    Molecular Neurobiology 51:1158–1167.

    https://doi.org/10.1007/s12035-014-8786-6

    • PubMed
    • Google Scholar
18. 1. Dawes P
    2. Payton A

    (2016)

    Genetics of Deafness

    84–96, Genetics of age-related hearing loss, Genetics of Deafness, Basel, Karger, 10.1159/000444565.

    • Google Scholar
19. 1. Di Meo S
    2. Reed TT
    3. Venditti P
    4. Victor VM

    (2016) Role of ROS and RNS sources in physiological and pathological conditions

    Oxidative Medicine and Cellular Longevity 2016:1–44.

    https://doi.org/10.1155/2016/1245049

    • Google Scholar
20. 1. Dorfman K
    2. Carrasco D
    3. Gruda M
    4. Ryan C
    5. Lira SA
    6. Bravo R

    (1996)

    Disruption of the erp/mkp-1 gene does not affect mouse development: normal MAP kinase activity in ERP/MKP-1-deficient fibroblasts

    Oncogene 13:925–931.

    • PubMed
    • Google Scholar
21. 1. Du C
    2. Gao Z
    3. Venkatesha VA
    4. Kalen AL
    5. Chaudhuri L
    6. Spitz DR
    7. Cullen JJ
    8. Oberley LW
    9. Goswami PC

    (2009) Mitochondrial ROS and radiation induced transformation in mouse embryonic fibroblasts

    Cancer Biology & Therapy 8:1962–1971.

    https://doi.org/10.4161/cbt.8.20.9648

    • PubMed
    • Google Scholar
22. 1. Dubno JR
    2. Eckert MA
    3. Lee FS
    4. Matthews LJ
    5. Schmiedt RA

    (2013) Classifying human audiometric phenotypes of age-related hearing loss from animal models

    Journal of the Association for Research in Otolaryngology 14:687–701.

    https://doi.org/10.1007/s10162-013-0396-x

    • PubMed
    • Google Scholar
23. 1. Elkon R
    2. Milon B
    3. Morrison L
    4. Shah M
    5. Vijayakumar S
    6. Racherla M
    7. Leitch CC
    8. Silipino L
    9. Hadi S
    10. Weiss-Gayet M
    11. Barras E
    12. Schmid CD
    13. Ait-Lounis A
    14. Barnes A
    15. Song Y
    16. Eisenman DJ
    17. Eliyahu E
    18. Frolenkov GI
    19. Strome SE
    20. Durand B
    21. Zaghloul NA
    22. Jones SM
    23. Reith W
    24. Hertzano R

    (2015) RFX transcription factors are essential for hearing in mice

    Nature Communications 6:8549.

    https://doi.org/10.1038/ncomms9549

    • PubMed
    • Google Scholar
24. 1. Espino Guarch M
    2. Font-Llitjós M
    3. Murillo-Cuesta S
    4. Errasti-Murugarren E
    5. Celaya AM
    6. Girotto G
    7. Vuckovic D
    8. Mezzavilla M
    9. Vilches C
    10. Bodoy S
    11. Sahún I
    12. González L
    13. Prat E
    14. Zorzano A
    15. Dierssen M
    16. Varela-Nieto I
    17. Gasparini P
    18. Palacín M
    19. Nunes V

    (2018) Mutations in L-type amino acid transporter-2 support SLC7A8 as a novel gene involved in age-related hearing loss

    eLife 7:e31511.

    https://doi.org/10.7554/eLife.31511

    • PubMed
    • Google Scholar
25. 1. Franklin CC
    2. Kraft AS

    (1997) Conditional expression of the mitogen-activated protein kinase (MAPK) phosphatase MKP-1 preferentially inhibits p38 MAPK and stress-activated protein kinase in U937 cells

    Journal of Biological Chemistry 272:16917–16923.

    https://doi.org/10.1074/jbc.272.27.16917

    • PubMed
    • Google Scholar
26. 1. Frye MD
    2. Yang W
    3. Zhang C
    4. Xiong B
    5. Hu BH

    (2017) Dynamic activation of basilar membrane macrophages in response to chronic sensory cell degeneration in aging mouse cochleae

    Hearing Research 344:125–134.

    https://doi.org/10.1016/j.heares.2016.11.003

    • PubMed
    • Google Scholar
27. 1. Fürst R
    2. Brueckl C
    3. Kuebler WM
    4. Zahler S
    5. Krötz F
    6. Görlach A
    7. Vollmar AM
    8. Kiemer AK

    (2005) Atrial natriuretic peptide induces mitogen-activated protein kinase phosphatase-1 in human endothelial cells via Rac1 and NAD(P)H oxidase/Nox2-activation

    Circulation Research 96:43–53.

    https://doi.org/10.1161/01.RES.0000151983.01148.06

    • PubMed
    • Google Scholar
28. 1. Gass P
    2. Eckhardt A
    3. Schröder H
    4. Bravo R
    5. Herdegen T

    (1996) Transient expression of the mitogen-activated protein kinase phosphatase MKP-1 (3CH134/ERP1) in the rat brain after limbic epilepsy

    Molecular Brain Research 41:74–80.

    https://doi.org/10.1016/0169-328X(96)00068-X

    • PubMed
    • Google Scholar
29. 1. Gupta J
    2. Nebreda AR

    (2015) Roles of p38α mitogen-activated protein kinase in mouse models of inflammatory diseases and cancer

    FEBS Journal 282:1841–1857.

    https://doi.org/10.1111/febs.13250

    • PubMed
    • Google Scholar
30. 1. Hickox AE
    2. Wong AC
    3. Pak K
    4. Strojny C
    5. Ramirez M
    6. Yates JR
    7. Ryan AF
    8. Savas JN

    (2017) Global analysis of protein expression of inner ear hair cells

    The Journal of Neuroscience 37:1320–1339.

    https://doi.org/10.1523/JNEUROSCI.2267-16.2016

    • PubMed
    • Google Scholar
31. 1. Hirose K
    2. Discolo CM
    3. Keasler JR
    4. Ransohoff R

    (2005) Mononuclear phagocytes migrate into the murine cochlea after acoustic trauma

    The Journal of Comparative Neurology 489:180–194.

    https://doi.org/10.1002/cne.20619

    • PubMed
    • Google Scholar
32. 1. Hoen PA
    2. Van der Lans CA
    3. Van Eck M
    4. Bijsterbosch MK
    5. Van Berkel TJ
    6. Twisk J

    (2003) Aorta of ApoE-deficient mice responds to atherogenic stimuli by a prelesional increase and subsequent decrease in the expression of antioxidant enzymes

    Circulation Research 93:262–269.

    https://doi.org/10.1161/01.RES.0000082978.92494.B1

    • PubMed
    • Google Scholar
33. 1. Hu BH
    2. Henderson D
    3. Nicotera TM

    (2002) Involvement of apoptosis in progression of cochlear lesion following exposure to intense noise

    Hearing Research 166:62–71.

    https://doi.org/10.1016/s0378-5955(02)00286-1

    • PubMed
    • Google Scholar
34. 1. Huang L
    2. Hou Y
    3. Wang L
    4. Xu X
    5. Guan Q
    6. Li X
    7. Chen Y
    8. Zhou W

    (2018) p38 inhibitor protects mitochondrial dysfunction by induction of DJ-1 mitochondrial translocation after subarachnoid hemorrhage

    Journal of Molecular Neuroscience 66:163–171.

    https://doi.org/10.1007/s12031-018-1131-1

    • PubMed
    • Google Scholar
35. 1. Huang CY
    2. Tan TH

    (2012) DUSPs, to MAP kinases and beyond

    Cell & Bioscience 2:24.

    https://doi.org/10.1186/2045-3701-2-24

    • PubMed
    • Google Scholar
36. 1. Hume CR
    2. Bratt DL
    3. Oesterle EC

    (2007) Expression of LHX3 and SOX2 during mouse inner ear development

    Gene Expression Patterns 7:798–807.

    https://doi.org/10.1016/j.modgep.2007.05.002

    • PubMed
    • Google Scholar
37. 1. Iskusnykh IY
    2. Popova TN
    3. Agarkov AA
    4. Pinheiro de Carvalho MÂ
    5. Rjevskiy SG

    (2013) Expression of glutathione peroxidase and glutathione reductase and level of free radical processes under toxic hepatitis in rats

    Journal of Toxicology 2013:870628.

    https://doi.org/10.1155/2013/870628

    • PubMed
    • Google Scholar
38. 1. Jamesdaniel S
    2. Hu B
    3. Kermany MH
    4. Jiang H
    5. Ding D
    6. Coling D
    7. Salvi R

    (2011) Noise induced changes in the expression of p38/MAPK signaling proteins in the sensory epithelium of the inner ear

    Journal of Proteomics 75:410–424.

    https://doi.org/10.1016/j.jprot.2011.08.007

    • PubMed
    • Google Scholar
39. 1. Jeanneteau F
    2. Deinhardt K
    3. Miyoshi G
    4. Bennett AM
    5. Chao MV

    (2010) The MAP kinase phosphatase MKP-1 regulates BDNF-induced axon branching

    Nature Neuroscience 13:1373–1379.

    https://doi.org/10.1038/nn.2655

    • PubMed
    • Google Scholar
40. 1. Jiang H
    2. Talaska AE
    3. Schacht J
    4. Sha SH

    (2007) Oxidative imbalance in the aging inner ear

    Neurobiology of Aging 28:1605–1612.

    https://doi.org/10.1016/j.neurobiolaging.2006.06.025

    • PubMed
    • Google Scholar
41. 1. Joo Y
    2. Hong O
    3. Wallhagen M

    (2016)

    The risk factors for Age-Related hearing loss: an integrative review

    Annals of Gerontology and Geriatric Research 3:.

    • Google Scholar
42. 1. Kalinec GM
    2. Lomberk G
    3. Urrutia RA
    4. Kalinec F

    (2017) Resolution of cochlear inflammation: novel target for preventing or ameliorating drug-, Noise- and Age-related hearing loss

    Frontiers in Cellular Neuroscience 11:192.

    https://doi.org/10.3389/fncel.2017.00192

    • PubMed
    • Google Scholar
43. 1. Kataya AR
    2. Schei E
    3. Lillo C

    (2015) MAP kinase phosphatase 1 harbors a novel PTS1 and is targeted to peroxisomes following stress treatments

    Journal of Plant Physiology 179:12–20.

    https://doi.org/10.1016/j.jplph.2015.03.002

    • PubMed
    • Google Scholar
44. 1. Kaur T
    2. Borse V
    3. Sheth S
    4. Sheehan K
    5. Ghosh S
    6. Tupal S
    7. Jajoo S
    8. Mukherjea D
    9. Rybak LP
    10. Ramkumar V

    (2016) Adenosine A1 receptor protects against cisplatin ototoxicity by suppressing the NOX3/STAT1 inflammatory pathway in the cochlea

    The Journal of Neuroscience 36:3962–3977.

    https://doi.org/10.1523/JNEUROSCI.3111-15.2016

    • PubMed
    • Google Scholar
45. 1. Kazak L
    2. Chouchani ET
    3. Stavrovskaya IG
    4. Lu GZ
    5. Jedrychowski MP
    6. Egan DF
    7. Kumari M
    8. Kong X
    9. Erickson BK
    10. Szpyt J
    11. Rosen ED
    12. Murphy MP
    13. Kristal BS
    14. Gygi SP
    15. Spiegelman BM

    (2017) UCP1 deficiency causes Brown fat respiratory chain depletion and sensitizes mitochondria to calcium overload-induced dysfunction

    PNAS 114:7981–7986.

    https://doi.org/10.1073/pnas.1705406114

    • PubMed
    • Google Scholar
46. 1. Kitahara T
    2. Li-Korotky HS
    3. Balaban CD

    (2005) Regulation of mitochondrial uncoupling proteins in mouse inner ear ganglion cells in response to systemic kanamycin challenge

    Neuroscience 135:639–653.

    https://doi.org/10.1016/j.neuroscience.2005.06.056

    • PubMed
    • Google Scholar
47. 1. Kurabi A
    2. Keithley EM
    3. Housley GD
    4. Ryan AF
    5. Wong AC

    (2017) Cellular mechanisms of noise-induced hearing loss

    Hearing Research 349:129–137.

    https://doi.org/10.1016/j.heares.2016.11.013

    • PubMed
    • Google Scholar
48. 1. Kusunoki T
    2. Cureoglu S
    3. Schachern PA
    4. Baba K
    5. Kariya S
    6. Paparella MM

    (2004) Age-Related histopathologic changes in the human cochlea: a temporal bone study

    Otolaryngology–Head and Neck Surgery 131:897–903.

    https://doi.org/10.1016/j.otohns.2004.05.022

    • Google Scholar
49. 1. Kuwano Y
    2. Kim HH
    3. Abdelmohsen K
    4. Pullmann R
    5. Martindale JL
    6. Yang X
    7. Gorospe M

    (2008) MKP-1 mRNA stabilization and translational control by RNA-binding proteins HuR and NF90

    Molecular and Cellular Biology 28:4562–4575.

    https://doi.org/10.1128/MCB.00165-08

    • PubMed
    • Google Scholar
50. 1. Kyriakis JM
    2. Avruch J

    (2012) Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update

    Physiological Reviews 92:689–737.

    https://doi.org/10.1152/physrev.00028.2011

    • PubMed
    • Google Scholar
51. 1. Lee KY

    (2013) Pathophysiology of age-related hearing loss (peripheral and central)

    Korean Journal of Audiology 17:45–49.

    https://doi.org/10.7874/kja.2013.17.2.45

    • PubMed
    • Google Scholar
52. 1. Li C
    2. Scott DA
    3. Hatch E
    4. Tian X
    5. Mansour SL

    (2007) Dusp6 (Mkp3) is a negative feedback regulator of FGF-stimulated ERK signaling during mouse development

    Development 134:167–176.

    https://doi.org/10.1242/dev.02701

    • PubMed
    • Google Scholar
53. 1. Lin YS
    2. Wang HY
    3. Huang DF
    4. Hsieh PF
    5. Lin MY
    6. Chou CH
    7. Wu IJ
    8. Huang GJ
    9. Gau SS
    10. Huang HS

    (2016) Neuronal splicing regulator RBFOX3 (NeuN) Regulates adult hippocampal neurogenesis and synaptogenesis

    PLOS ONE 11:e0164164.

    https://doi.org/10.1371/journal.pone.0164164

    • PubMed
    • Google Scholar
54. 1. Liu H
    2. Pecka JL
    3. Zhang Q
    4. Soukup GA
    5. Beisel KW
    6. He DZ

    (2014) Characterization of transcriptomes of cochlear inner and outer hair cells

    Journal of Neuroscience 34:11085–11095.

    https://doi.org/10.1523/JNEUROSCI.1690-14.2014

    • PubMed
    • Google Scholar
55. 1. López-Otín C
    2. Blasco MA
    3. Partridge L
    4. Serrano M
    5. Kroemer G

    (2013) The hallmarks of aging

    Cell 153:1194–1217.

    https://doi.org/10.1016/j.cell.2013.05.039

    • PubMed
    • Google Scholar
56. 1. Maeda Y
    2. Fukushima K
    3. Omichi R
    4. Kariya S
    5. Nishizaki K

    (2013) Time courses of changes in Phospho- and total- MAP kinases in the cochlea after intense noise exposure

    PLOS ONE 8:e58775.

    https://doi.org/10.1371/journal.pone.0058775

    • PubMed
    • Google Scholar
57. 1. Makary CA
    2. Shin J
    3. Kujawa SG
    4. Liberman MC
    5. Merchant SN

    (2011) Age-related primary cochlear neuronal degeneration in human temporal bones

    Journal of the Association for Research in Otolaryngology 12:711–717.

    https://doi.org/10.1007/s10162-011-0283-2

    • PubMed
    • Google Scholar
58. 1. Manea SA
    2. Constantin A
    3. Manda G
    4. Sasson S
    5. Manea A

    (2015) Regulation of nox enzymes expression in vascular pathophysiology: focusing on transcription factors and epigenetic mechanisms

    Redox Biology 5:358–366.

    https://doi.org/10.1016/j.redox.2015.06.012

    • PubMed
    • Google Scholar
59. 1. Martínez-Vega R
    2. Garrido F
    3. Partearroyo T
    4. Cediel R
    5. Zeisel SH
    6. Martínez-Álvarez C
    7. Varela-Moreiras G
    8. Varela-Nieto I
    9. Pajares MA

    (2015a) Folic acid deficiency induces premature hearing loss through mechanisms involving cochlear oxidative stress and impairment of homocysteine metabolism

    The FASEB Journal 29:418–432.

    https://doi.org/10.1096/fj.14-259283

    • PubMed
    • Google Scholar
60. 1. Martínez-Vega R
    2. Partearroyo T
    3. Vallecillo N
    4. Varela-Moreiras G
    5. Pajares MA
    6. Varela-Nieto I

    (2015b) Long-term omega-3 fatty acid supplementation prevents expression changes in cochlear homocysteine metabolism and ameliorates progressive hearing loss in C57BL/6J mice

    The Journal of Nutritional Biochemistry 26:1424–1433.

    https://doi.org/10.1016/j.jnutbio.2015.07.011

    • PubMed
    • Google Scholar
61. Book

    1. Miller J

    (2015)

    Free Radicals in ENT Pathology

    Springer.

    • Google Scholar
62. 1. Möhrle D
    2. Ni K
    3. Varakina K
    4. Bing D
    5. Lee SC
    6. Zimmermann U
    7. Knipper M
    8. Rüttiger L

    (2016) Loss of auditory sensitivity from inner hair cell synaptopathy can be centrally compensated in the young but not old brain

    Neurobiology of Aging 44:173–184.

    https://doi.org/10.1016/j.neurobiolaging.2016.05.001

    • PubMed
    • Google Scholar
63. 1. Mukherjea D
    2. Whitworth CA
    3. Nandish S
    4. Dunaway GA
    5. Rybak LP
    6. Ramkumar V

    (2006) Expression of the kidney injury molecule 1 in the rat cochlea and induction by cisplatin

    Neuroscience 139:733–740.

    https://doi.org/10.1016/j.neuroscience.2005.12.044

    • PubMed
    • Google Scholar
64. 1. Mukherjea D
    2. Jajoo S
    3. Sheehan K
    4. Kaur T
    5. Sheth S
    6. Bunch J
    7. Perro C
    8. Rybak LP
    9. Ramkumar V

    (2011) NOX3 NADPH oxidase couples transient receptor potential vanilloid 1 to signal transducer and activator of transcription 1-mediated inflammation and hearing loss

    Antioxidants & Redox Signaling 14:999–1010.

    https://doi.org/10.1089/ars.2010.3497

    • PubMed
    • Google Scholar
65. 1. Mullen LM
    2. Pak KK
    3. Chavez E
    4. Kondo K
    5. Brand Y
    6. Ryan AF

    (2012) Ras/p38 and PI3K/Akt but not mek/Erk signaling mediate BDNF-induced neurite formation on neonatal cochlear spiral ganglion explants

    Brain Research 1430:25–34.

    https://doi.org/10.1016/j.brainres.2011.10.054

    • PubMed
    • Google Scholar
66. 1. Müller U
    2. Barr-Gillespie PG

    (2015) New treatment options for hearing loss

    Nature Reviews Drug Discovery 14:346–365.

    https://doi.org/10.1038/nrd4533

    • PubMed
    • Google Scholar
67. 1. Murillo-Cuesta S
    2. Contreras J
    3. Cediel R
    4. Varela-Nieto I

    (2010) Comparison of different aminoglycoside antibiotic treatments to refine ototoxicity studies in adult mice

    Laboratory Animals 44:124–131.

    https://doi.org/10.1258/la.2009.009046

    • PubMed
    • Google Scholar
68. 1. Murillo-Cuesta S
    2. Rodríguez-de la Rosa L
    3. Contreras J
    4. Celaya AM
    5. Camarero G
    6. Rivera T
    7. Varela-Nieto I

    (2015) Transforming growth factor beta1 inhibition protects from noise-induced hearing loss

    Frontiers in Aging Neuroscience 7:32.

    https://doi.org/10.3389/fnagi.2015.00032

    • PubMed
    • Google Scholar
69. 1. Nadol JB

    (1979) Electron microscopic findings in Presbycusic degeneration of the basal turn of the human cochlea

    Otolaryngology–Head and Neck Surgery 87:818–836.

    https://doi.org/10.1177/019459987908700617

    • Google Scholar
70. 1. Nelson EG
    2. Hinojosa R

    (2006) Presbycusis: a human temporal bone study of individuals with downward sloping audiometric patterns of hearing loss and review of the literature

    The Laryngoscope 116:1–12.

    https://doi.org/10.1097/01.mlg.0000236089.44566.62

    • PubMed
    • Google Scholar
71. 1. Nóbrega-Pereira S
    2. Fernandez-Marcos PJ
    3. Brioche T
    4. Gomez-Cabrera MC
    5. Salvador-Pascual A
    6. Flores JM
    7. Viña J
    8. Serrano M

    (2016) G6PD protects from oxidative damage and improves healthspan in mice

    Nature Communications 7:10894.

    https://doi.org/10.1038/ncomms10894

    • PubMed
    • Google Scholar
72. 1. Ohlemiller KK
    2. Dahl AR
    3. Gagnon PM

    (2010) Divergent aging characteristics in CBA/J and CBA/CaJ mouse cochleae

    Journal of the Association for Research in Otolaryngology 11:605–623.

    https://doi.org/10.1007/s10162-010-0228-1

    • PubMed
    • Google Scholar
73. 1. Owens DM
    2. Keyse SM

    (2007) Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases

    Oncogene 26:3203–3213.

    https://doi.org/10.1038/sj.onc.1210412

    • PubMed
    • Google Scholar
74. 1. Palmero I
    2. Serrano M

    (2001) Induction of senescence by oncogenic ras

    Methods in Enzymology 333:247–256.

    https://doi.org/10.1016/s0076-6879(01)33060-4

    • PubMed
    • Google Scholar
75. 1. Pan H
    2. Song Q
    3. Huang Y
    4. Wang J
    5. Chai R
    6. Yin S
    7. Wang J

    (2017) Auditory neuropathy after damage to cochlear spiral ganglion neurons in mice resulting from conditional expression of diphtheria toxin receptors

    Scientific Reports 7:6409.

    https://doi.org/10.1038/s41598-017-06600-6

    • PubMed
    • Google Scholar
76. 1. Parker A
    2. Cross SH
    3. Jackson IJ
    4. Hardisty-Hughes R
    5. Morse S
    6. Nicholson G
    7. Coghill E
    8. Bowl MR
    9. Brown SD

    (2015) The goya mouse mutant reveals distinct newly identified roles for MAP3K1 in the development and survival of cochlear sensory hair cells

    Disease Models & Mechanisms 8:1555–1568.

    https://doi.org/10.1242/dmm.023176

    • PubMed
    • Google Scholar
77. 1. Patterson KI
    2. Brummer T
    3. O'brien PM
    4. Daly RJ

    (2009) Dual-specificity phosphatases: critical regulators with diverse cellular targets

    Biochemical Journal 418:475–489.

    https://doi.org/10.1042/BJ20082234

    • Google Scholar
78. 1. Poirrier AL
    2. Pincemail J
    3. Van Den Ackerveken P
    4. Lefebvre PP
    5. Malgrange B

    (2010) Oxidative stress in the cochlea: an update

    Current Medicinal Chemistry 17:3591–3604.

    https://doi.org/10.2174/092986710792927895

    • PubMed
    • Google Scholar
79. 1. Ren HM
    2. Ren J
    3. Liu W

    (2013) Recognition and control of the progression of age-related hearing loss

    Rejuvenation Research 16:475–486.

    https://doi.org/10.1089/rej.2013.1435

    • PubMed
    • Google Scholar
80. 1. Riquelme R
    2. Cediel R
    3. Contreras J
    4. la Rosa Lourdes RD
    5. Murillo-Cuesta S
    6. Hernandez-Sanchez C
    7. Zubeldia JM
    8. Cerdan S
    9. Varela-Nieto I

    (2010) A comparative study of age-related hearing loss in wild type and insulin-like growth factor I deficient mice

    Frontiers in Neuroanatomy 4:27.

    https://doi.org/10.3389/fnana.2010.00027

    • PubMed
    • Google Scholar
81. 1. Rodríguez-de la Rosa L
    2. Sánchez-Calderón H
    3. Contreras J
    4. Murillo-Cuesta S
    5. Falagan S
    6. Avendaño C
    7. Dopazo J
    8. Varela-Nieto I
    9. Milo M

    (2015) Comparative gene expression study of the vestibular organ of the Igf1 deficient mouse using whole-transcript arrays

    Hearing Research 330:62–77.

    https://doi.org/10.1016/j.heares.2015.08.016

    • PubMed
    • Google Scholar
82. 1. Sakamoto A
    2. Kuroda Y
    3. Kanzaki S
    4. Matsuo K

    (2017) Dissection of the auditory Bulla in postnatal mice: isolation of the middle ear bones and histological analysis

    Journal of Visualized Experiments.

    https://doi.org/10.3791/55054

    • PubMed
    • Google Scholar
83. 1. Sanchez-Calderon H
    2. Rodriguez-de la Rosa L
    3. Milo M
    4. Pichel JG
    5. Holley M
    6. Varela-Nieto I

    (2010) RNA microarray analysis in prenatal mouse cochlea reveals novel IGF-I target genes: implication of MEF2 and FOXM1 transcription factors

    PLOS ONE 5:e8699.

    https://doi.org/10.1371/journal.pone.0008699

    • PubMed
    • Google Scholar
84. 1. Sánchez-Perez I
    2. Murguía JR
    3. Perona R

    (1998) Cisplatin induces a persistent activation of JNK that is related to cell death

    Oncogene 16:533–540.

    https://doi.org/10.1038/sj.onc.1201578

    • PubMed
    • Google Scholar
85. 1. Sanz L
    2. Murillo-Cuesta S
    3. Cobo P
    4. Cediel-Algovia R
    5. Contreras J
    6. Rivera T
    7. Varela-Nieto I
    8. Avendaño C

    (2015) Swept-sine noise-induced damage as a hearing loss model for preclinical assays

    Frontiers in Aging Neuroscience 7:7.

    https://doi.org/10.3389/fnagi.2015.00007

    • PubMed
    • Google Scholar
86. 1. Scheffer DI
    2. Shen J
    3. Corey DP
    4. Chen Z-Y

    (2015) Gene Expression by Mouse Inner Ear Hair Cells during Development

    Journal of Neuroscience 35:6366–6380.

    https://doi.org/10.1523/JNEUROSCI.5126-14.2015

    • Google Scholar
87. 1. Schindelin J
    2. Arganda-Carreras I
    3. Frise E
    4. Kaynig V
    5. Longair M
    6. Pietzsch T
    7. Preibisch S
    8. Rueden C
    9. Saalfeld S
    10. Schmid B
    11. Tinevez J-Y
    12. White DJ
    13. Hartenstein V
    14. Eliceiri K
    15. Tomancak P
    16. Cardona A

    (2012) Fiji: an open-source platform for biological-image analysis

    Nature Methods 9:676–682.

    https://doi.org/10.1038/nmeth.2019

    • Google Scholar
88. 1. Sha SH
    2. Taylor R
    3. Forge A
    4. Schacht J

    (2001) Differential vulnerability of basal and apical hair cells is based on intrinsic susceptibility to free radicals

    Hearing Research 155:1–8.

    https://doi.org/10.1016/S0378-5955(01)00224-6

    • PubMed
    • Google Scholar
89. 1. Sha SH
    2. Chen FQ
    3. Schacht J

    (2009) Activation of cell death pathways in the inner ear of the aging CBA/J mouse

    Hearing Research 254:92–99.

    https://doi.org/10.1016/j.heares.2009.04.019

    • PubMed
    • Google Scholar
90. 1. Shearer AE
    2. Hildebrand MS
    3. Smith RJH

    (1993)

    GeneReviews

    Hereditary Hearing Loss and Deafness Overview, GeneReviews, Seattle, University of Washington.

    • Google Scholar
91. 1. Sikalidis AK
    2. Mazor KM
    3. Lee JI
    4. Roman HB
    5. Hirschberger LL
    6. Stipanuk MH

    (2014) Upregulation of capacity for glutathione synthesis in response to amino acid deprivation: regulation of glutamate-cysteine ligase subunits

    Amino Acids 46:1285–1296.

    https://doi.org/10.1007/s00726-014-1687-1

    • PubMed
    • Google Scholar
92. 1. Steevens AR
    2. Sookiasian DL
    3. Glatzer JC
    4. Kiernan AE

    (2017) SOX2 is required for inner ear neurogenesis

    Scientific Reports 7:4086.

    https://doi.org/10.1038/s41598-017-04315-2

    • PubMed
    • Google Scholar
93. 1. Tabuchi K
    2. Oikawa K
    3. Hoshino T
    4. Nishimura B
    5. Hayashi K
    6. Yanagawa T
    7. Warabi E
    8. Ishii T
    9. Tanaka S
    10. Hara A

    (2010) Cochlear protection from acoustic injury by inhibitors of p38 mitogen-activated protein kinase and sequestosome 1 stress protein

    Neuroscience 166:665–670.

    https://doi.org/10.1016/j.neuroscience.2009.12.038

    • PubMed
    • Google Scholar
94. 1. Takada Y
    2. Beyer LA
    3. Swiderski DL
    4. O'Neal AL
    5. Prieskorn DM
    6. Shivatzki S
    7. Avraham KB
    8. Raphael Y

    (2014) Connexin 26 null mice exhibit spiral ganglion degeneration that can be blocked by BDNF gene therapy

    Hearing Research 309:124–135.

    https://doi.org/10.1016/j.heares.2013.11.009

    • PubMed
    • Google Scholar
95. 1. Takeshita S
    2. Inoue N
    3. Ueyama T
    4. Kawashima S
    5. Yokoyama M

    (2000) Shear stress enhances glutathione peroxidase expression in endothelial cells

    Biochemical and Biophysical Research Communications 273:66–71.

    https://doi.org/10.1006/bbrc.2000.2898

    • PubMed
    • Google Scholar
96. 1. Talwar H
    2. Bauerfeld C
    3. Bouhamdan M
    4. Farshi P
    5. Liu Y
    6. Samavati L

    (2017) MKP-1 negatively regulates LPS-mediated IL-1β production through p38 activation and HIF-1α expression

    Cellular Signalling 34:1–10.

    https://doi.org/10.1016/j.cellsig.2017.02.018

    • PubMed
    • Google Scholar
97. 1. Taylor DM
    2. Moser R
    3. Régulier E
    4. Breuillaud L
    5. Dixon M
    6. Beesen AA
    7. Elliston L
    8. Silva Santos MF
    9. Kim J
    10. Jones L
    11. Goldstein DR
    12. Ferrante RJ
    13. Luthi-Carter R

    (2013) MAP kinase phosphatase 1 (MKP-1/DUSP1) is neuroprotective in Huntington's disease via additive effects of JNK and p38 inhibition

    Journal of Neuroscience 33:2313–2325.

    https://doi.org/10.1523/JNEUROSCI.4965-11.2013

    • PubMed
    • Google Scholar
98. 1. Tian L
    2. Shao X
    3. Xie Y
    4. Wang Q
    5. Che X
    6. Zhang M
    7. Xu W
    8. Xu Y
    9. Mou S
    10. Ni Z

    (2017) Kidney injury Molecule-1 is elevated in nephropathy and mediates macrophage activation via the mapk signalling pathway

    Cellular Physiology and Biochemistry 41:769–783.

    https://doi.org/10.1159/000458737

    • PubMed
    • Google Scholar
99. 1. Uchida Y
    2. Sugiura S
    3. Ando F
    4. Nakashima T
    5. Shimokata H

    (2011) Molecular genetic epidemiology of age-related hearing impairment

    Auris Nasus Larynx 38:657–665.

    https://doi.org/10.1016/j.anl.2011.02.005

    • PubMed
    • Google Scholar
100. 1. Unal M
     2. Tamer L
     3. Doğruer ZN
     4. Yildirim H
     5. Vayisoğlu Y
     6. Camdeviren H

     (2005) N-acetyltransferase 2 gene polymorphism and presbycusis

     The Laryngoscope 115:2238–2241.

     https://doi.org/10.1097/01.mlg.0000183694.10583.12

     • PubMed
     • Google Scholar
101. 1. Urness LD
     2. Li C
     3. Wang X
     4. Mansour SL

     (2008) Expression of ERK signaling inhibitors Dusp6, Dusp7, and Dusp9 during mouse ear development

     Developmental Dynamics 237:163–169.

     https://doi.org/10.1002/dvdy.21380

     • PubMed
     • Google Scholar
102. 1. Van Eyken E
     2. Van Camp G
     3. Fransen E
     4. Topsakal V
     5. Hendrickx JJ
     6. Demeester K
     7. Van de Heyning P
     8. Mäki-Torkko E
     9. Hannula S
     10. Sorri M
     11. Jensen M
     12. Parving A
     13. Bille M
     14. Baur M
     15. Pfister M
     16. Bonaconsa A
     17. Mazzoli M
     18. Orzan E
     19. Espeso A
     20. Stephens D
     21. Verbruggen K
     22. Huyghe J
     23. Dhooge I
     24. Huygen P
     25. Kremer H
     26. Cremers CW
     27. Kunst S
     28. Manninen M
     29. Pyykkö I
     30. Lacava A
     31. Steffens M
     32. Wienker TF
     33. Van Laer L

     (2007) Contribution of the N-acetyltransferase 2 polymorphism NAT2*6A to age-related hearing impairment

     Journal of Medical Genetics 44:570–578.

     https://doi.org/10.1136/jmg.2007.049205

     • PubMed
     • Google Scholar
103. 1. Ventura JJ
     2. Tenbaum S
     3. Perdiguero E
     4. Huth M
     5. Guerra C
     6. Barbacid M
     7. Pasparakis M
     8. Nebreda AR

     (2007) p38alpha MAP kinase is essential in lung stem and progenitor cell proliferation and differentiation

     Nature Genetics 39:750–758.

     https://doi.org/10.1038/ng2037

     • PubMed
     • Google Scholar
104. 1. Verschuur C
     2. Agyemang-Prempeh A
     3. Newman TA

     (2014) Inflammation is associated with a worsening of presbycusis: evidence from the MRC national study of hearing

     International Journal of Audiology 53:469–475.

     https://doi.org/10.3109/14992027.2014.891057

     • PubMed
     • Google Scholar
105. 1. Vlajkovic SM
     2. Lin SC
     3. Wong AC
     4. Wackrow B
     5. Thorne PR

     (2013) Noise-induced changes in expression levels of NADPH oxidases in the cochlea

     Hearing Research 304:145–152.

     https://doi.org/10.1016/j.heares.2013.07.012

     • PubMed
     • Google Scholar
106. 1. Wang J
     2. Ruel J
     3. Ladrech S
     4. Bonny C
     5. van de Water TR
     6. Puel JL

     (2007) Inhibition of the c-Jun N-terminal kinase-mediated mitochondrial cell death pathway restores auditory function in sound-exposed animals

     Molecular Pharmacology 71:654–666.

     https://doi.org/10.1124/mol.106.028936

     • PubMed
     • Google Scholar
107. 1. Wang J
     2. Zhang B
     3. Jiang H
     4. Zhang L
     5. Liu D
     6. Xiao X
     7. Ma H
     8. Luo X
     9. Bojrab D
     10. Hu Z

     (2013) Myelination of the postnatal mouse cochlear nerve at the peripheral-central nervous system transitional zone

     Frontiers in Pediatrics 1:43.

     https://doi.org/10.3389/fped.2013.00043

     • PubMed
     • Google Scholar
108. Website

     1. WHO

     (2018) Deafness and hearing loss

     Accessed March 15, 2018.

     https://www.who.int/news-room/fact-sheets/detail/deafness-and-hearing-loss
109. 1. Wong AC
     2. Ryan AF

     (2015) Mechanisms of sensorineural cell damage, death and survival in the cochlea

     Frontiers in Aging Neuroscience 7:58.

     https://doi.org/10.3389/fnagi.2015.00058

     • PubMed
     • Google Scholar
110. 1. Yang CH
     2. Schrepfer T
     3. Schacht J

     (2015) Age-related hearing impairment and the triad of acquired hearing loss

     Frontiers in Cellular Neuroscience 9:276.

     https://doi.org/10.3389/fncel.2015.00276

     • PubMed
     • Google Scholar
111. 1. Yu Q
     2. Du F
     3. Douglas JT
     4. Yu H
     5. Yan SS
     6. Yan SF

     (2017) Mitochondrial Dysfunction Triggers Synaptic Deficits via Activation of p38 MAP Kinase Signaling in Differentiated Alzheimer's Disease Trans-Mitochondrial Cybrid Cells

     Journal of Alzheimer's Disease 59:223–239.

     https://doi.org/10.3233/JAD-170283

     • PubMed
     • Google Scholar
112. 1. Zheng J
     2. Shen W
     3. He DZ
     4. Long KB
     5. Madison LD
     6. Dallos P

     (2000) Prestin is the motor protein of cochlear outer hair cells

     Nature 405:149–155.

     https://doi.org/10.1038/35012009

     • PubMed
     • Google Scholar

Author details

1. Adelaida M Celaya

   1. Institute for Biomedical Research “Alberto Sols” (IIBM), Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain
   2. Centre for Biomedical Network Research on Rare Diseases (CIBERER), CIBER, ISCIII, Madrid, Spain

   Contribution

   Data curation, Formal analysis, Supervision, Investigation, Visualization, Writing—original draft

   For correspondence

   acelaya@iib.uam.es

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-0757-6163

2. Isabel Sánchez-Pérez

   1. Institute for Biomedical Research “Alberto Sols” (IIBM), Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain
   2. Centre for Biomedical Network Research on Rare Diseases (CIBERER), CIBER, ISCIII, Madrid, Spain
   3. Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain
   4. Biochemistry Department, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain
   5. Biomedicine Unit UCLM-CSIC, Madrid, Spain

   Contribution

   Data curation, Formal analysis, Investigation, Visualization, Writing—review and editing

   Contributed equally with

   Jose M Bermúdez-Muñoz

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-4829-201X

3. Jose M Bermúdez-Muñoz

   1. Institute for Biomedical Research “Alberto Sols” (IIBM), Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain
   2. Centre for Biomedical Network Research on Rare Diseases (CIBERER), CIBER, ISCIII, Madrid, Spain

   Contribution

   Data curation, Formal analysis, Investigation, Visualization, Writing—review and editing

   Contributed equally with

   Isabel Sánchez-Pérez

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-6034-9285

4. Lourdes Rodríguez-de la Rosa

   1. Institute for Biomedical Research “Alberto Sols” (IIBM), Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain
   2. Centre for Biomedical Network Research on Rare Diseases (CIBERER), CIBER, ISCIII, Madrid, Spain
   3. Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain

   Contribution

   Data curation, Formal analysis, Investigation

   Competing interests

   No competing interests declared

5. Laura Pintado-Berninches

   1. Institute for Biomedical Research “Alberto Sols” (IIBM), Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain
   2. Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain

   Contribution

   Resources, Methodology, Given final approval of the version to be published

   Competing interests

   No competing interests declared

6. Rosario Perona

   1. Institute for Biomedical Research “Alberto Sols” (IIBM), Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain
   2. Centre for Biomedical Network Research on Rare Diseases (CIBERER), CIBER, ISCIII, Madrid, Spain
   3. Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain

   Contribution

   Resources, Supervision, Funding acquisition, Writing—review and editing

   Competing interests

   No competing interests declared

7. Silvia Murillo-Cuesta

   1. Institute for Biomedical Research “Alberto Sols” (IIBM), Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain
   2. Centre for Biomedical Network Research on Rare Diseases (CIBERER), CIBER, ISCIII, Madrid, Spain

   Contribution

   Data curation, Formal analysis, Investigation

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-8706-4327

8. Isabel Varela-Nieto

   1. Institute for Biomedical Research “Alberto Sols” (IIBM), Spanish National Research Council-Autonomous University of Madrid (CSIC-UAM), Madrid, Spain
   2. Centre for Biomedical Network Research on Rare Diseases (CIBERER), CIBER, ISCIII, Madrid, Spain

   Contribution

   Conceptualization, Formal analysis, Supervision, Funding acquisition, Visualization, Writing—original draft, Project administration

   For correspondence

   ivarela@iib.uam.es

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-3077-0500

• 2,330

  views

• 306

  downloads

• 22

  citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.