Improving glucose metabolism in the auditory cortex delays the aging of auditory function of guinea pig
Introduction
Age-related hearing loss (ARHL), also known as presbycusis, is defined as a bilateral, symmetrical, progressive sensorineural hearing loss with aging, which is most obvious at the higher frequencies (Bowl and Dawson, 2018). According to the results of the Second China National Sample Survey on Disability, there may be approximately 20,454,000 people with ARHL in China (Sun et al., 2008). Hearing impairment can affect the quality of life, and has a great negative effect on the communication. Moreover, it may also result in the occurrence of dementia, cognitive impairment and Alzheimer's disease (Loughrey et al., 2018; Panza et al., 2015). In addition, it is estimated that the direct medical costs for the first year treatment of ARHL will exceed $51 billion by 2030 in the United States (Stucky et al., 2010). Given the significant social and welfare burden that results from ARHL, there is an urgent need for the continuous researches on the mechanism and therapeutic interventions of ARHL.
Aging is often considered to affect both the peripheral and central auditory systems (Occelli et al., 2019). Auditory cortex is a part of the central auditory system and plays an important role in auditory function. Up to now, the changes and mechanisms of auditory cortex have not been fully elucidated in response to ARHL. Aging is associated with multiple changes in auditory cortex response patterns including increased and less variable response magnitude, a larger response range, and reduced sensitivity to temporal context (Herrmann et al., 2016). Energy metabolism dysfunction is a major key to the aging process of ARHL (Coling et al., 2009; Kim et al., 2014). Glucose metabolism decreases in the caudate nucleus of the brain with normal aging process (Shen et al., 2012), and the same change may take place in the auditory cortex of the guinea pigs with ARHL. As a non-invasive tomography technique, PET/CT is an effective and intuitive way to detect brain glucose metabolism (Koba et al., 2013). 18F-FDG PET/CT is widely used to image neural activation in the brain (Paul et al., 2009; Shimoji et al., 2004). However, there are relatively few reports about the nature of the glucose metabolism of the auditory cortex of the guinea pigs with d-galactose-induced ARHL by micro PET/CT.
Proteomics is the research on protein components of the genome, cells, tissues and organs, which include structural and functional proteomics (Thalmann, 2001). The proteomics approach was used to identify the proteins participated in cisplatin-induced ototoxicity (Waissbluth et al., 2017), find biomarkers for noninvasive inner ear diagnostics, and illustrate molecular profiles of sensorineural hearing loss (Schmitt et al., 2017). Until now, we know very little about the proteome changes that occur in the auditory cortex of guinea pigs with ARHL.
As a therapy of Traditional Chinese Medicine, acupuncture can reverse sudden sensorineural hearing loss and ARHL (Liu et al., 2017; Zhang et al., 2015). Furthermore, glucose metabolism increased in the brain of healthy volunteers after acupuncture (Park et al., 2010). Our previous study has reported that electroacupuncturing at Tinggong (SI19) and Yifeng (SJ17) could improve glucose metabolism in the auditory cortex of the guinea pig (Tu et al., 2015). Therefore, the study that delays the aging of auditory function by regulating the glucose metabolism in the auditory cortex is beneficial to understand the mechanism of ARHL.
The present study was to investigate whether improving glucose metabolism in the auditory cortex can delay the aging of auditory function of guinea pigs with d-galactose-induced ARHL. The ARHL model was established by subcutaneous injection of d-galactose. Auditory function was assessed by auditory brainstem response (ABR), glucose metabolism was detected by micro PET/CT, and the differential proteins were analyzed by MALDI-TOF-MS.
Section snippets
Animal models
There were four groups. Thirty male guinea pigs(initial body weight 230-400 g, 4 months old) with normal acoustic pinna reflex were randomly divided into three groups including the d-galactose group (DG, n = 10), d-galactose and electroacupuncture group (DEG, n = 10), and control group (CG, n = 10). The elderly group (EG) included ten male guinea pigs (initial body weight 500−700 g, 18 months old). The guinea pigs were purchased from laboratory animal center of Southwest Medical University.
Changes in the ABR threshold
The ABR threshold of guinea pigs were tested in the CG, EG, DG and DEG respectively, and the hearing threshold on both ears at different frequencies of 4 and 8 kHz were recorded (Fig. 1). The averages of ABR threshold between CG, EG, DE and DEG were as follows:37.0 ± 5.4, 80.5 ± 6.4, 76.5 ± 3.4 and 45.5 ± 6.9 dB SPL in the left ear at the frequencies of 4 kHz; 39.0 ± 3.2, 79.5 ± 7.2, 74.5 ± 4.4 and 45.0 ± 6.2 dB SPL in the right ear at the frequencies of 4 kHz; 35.0 ± 3.3, 77.2 ± 8.5, 77.0 ±
Decrease of glucose metabolism promotes the aging of auditory function
Mice treated with d-galactose exhibited oxidant damage in the blood, brain and liver, and d-galactose treatment in mice was confirmed as a successful mimetic aging model (Ho et al., 2003). d-galactose injection induces multiple molecular and functional changes, oxidative stress, mitochondrial dysfunction and abnormal apoptosis in the brain similar to natural aging (Cai et al., 2020). Eight weeks of d-galactose treatment successfully established an ideal mimetic Sprague‑Dawley rat model of
Conclusions
The imbalance of glucose metabolism in the auditory cortex may be an important factor in the aging of the auditory function of the guinea pig with ARHL, and the seven proteins related to energy metabolism may be involved in the process. Improving the glucose metabolism and upregulating these proteins expression in the auditory cortex by acupuncturing at Tinggong (SI19) and Yifeng (SJ17) can prevent the aging of auditory function of guinea pigs with ARHL induced by d-galactos.
Acknowledgments
This work was supported by the Health Commission of Sichuan Province (No. 19PJ150), Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province (No. HYX19003), Health Committee Office of Sichuan Province (No. 20191501) and National Students’ Platform for Innovation and Entrepreneurship Training Program (No. 201710632014).
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These authors are joint first authors.
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Permanent address: Department of Otolaryngology-Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, Taiping Avenue 25, Luzhou 646000, PR China.