Besides Huntington's disease, does brain-type creatine kinase play a role in other forms of hearing impairment resulting from a common pathological cause?

Abstract

Hearing impairment following cochlear damage due to noise trauma, ototoxicity caused by aminoglycoside antibiotics, or age-related cochlear degeneration was linked to a common pathogenesis involving the formation of reactive oxygen species (ROS). Cochleae are more vulnerable to oxidative stress than other organs because of the high metabolic demands of their mechanosensory hair cells in response to sound stimulation. We recently showed that patients and mice with Huntington's disease (HD) have hearing impairment and that the dysregulated phosphocreatine (PCr)-creatine kinase (CK) system may account for this auditory dysfunction. Given the importance of noninvasive biomarkers and the easy access of hearing tests, the symptom of hearing loss in HD patients may serve as a useful clinical indicator of disease onset and progression of HD. We also showed that dietary creatine supplementation rescued the impaired PCr-CK system and improved the expression of cochlear brain-type creatine kinase (CKB) in HD mice, thereby restoring their hearing. Because creatine is an antioxidant, we postulated that creatine might enhance expression of CKB by reducing oxidative stress. In addition to HD-related hearing impairment, inferior CKB expression and/or an impaired PCr-CK system may also play an important role in other hearing impairments caused by elevated levels of ROS. Most importantly, dietary supplements may be beneficial to patients with these hearing deficiencies.

Figure 1. Proposed model for the pathogenesis of hearing impairment in Huntington's disease (HD).

Mitochondrial creatine kinase (CKMT1) phosphorylates creatine (Cr) and converts it to phosphocreatine (PCr), while brain-type creatine kinase (CKB) regenerates ATP from PCr. Because the stereocilia contain no mitochondria, the PCr-CK system plays a critical role in hair bundles of hair cells. Expression of mutant Huntingtin (Htt) in hair cells impairs the functioning of mitochondria, suppresses the expression of CKB, and elevates levels of reactive oxygen species (ROS). Creatine supplementation in HD mice ameliorates the reduced expression of CKB via an unidentified pathway, and subsequently improves the hearing impairment in HD mice.