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Hair cell (HC) degeneration causes hearing loss in millions of people worldwide. Aminoglycoside exposure is one major cause of sensory HC damage. Aminoglycosides generate free radicals within the inner ear, permanently damaging sensory cells, and thus causing hearing loss. Hearing protection requires strategies to overcome the apparently irreversible loss of HCs in mammals. The nuclear factor of activated T cells (NFAT) inhibitor 11R‐VIVIT reportedly protects HCs from gentamicin toxicity. Here we investigated whether the combination of 11R‐VIVIT with the antioxidant L‐carnitine or N‐acetylcysteine could protect mouse cochlear HCs from gentamicin damage. Compared to single‐component treatment, combined treatment with 11R‐VIVIT plus L‐carnitine yielded significant protection from gentamicin, and 11R‐VIVIT plus N‐acetylcysteine provided almost complete protection of HCs from gentamicin. Caspase activity in organ of Corti was significantly reduced by combined treatment with 11R‐VIVIT + N‐acetylcysteine + gentamicin, compared to 11R‐VIVIT + gentamicin or gentamicin alone. Analysis of relative gene expression by qPCR revealed down‐regulation of the pro‐apoptotic genes Fasl and Casp9, and up‐regulation of the antioxidant genes Hmox1 and Nrf2 after treatment with 11R‐VIVIT + N‐acetylcysteine + gentamicin, compared to single‐compound treatment or gentamicin alone in cultures. Selective NFAT inhibition by 11R‐VIVIT may be a good strategy for preventing gentamicin‐induced HC damage. L‐carnitine and N‐acetylcysteine, with their ROS‐reducing properties, contribute to the synergistic effectiveness with 11R‐VIVIT by decreasing ROS‐induced NFAT translocation. Our data suggest that a combined approach of NFAT inhibition together with an antioxidant, like N‐acetylcysteine, could be useful for hearing loss treatment and/or prevention. Cover Image for this issue: https://doi.org/10.1111/jnc.14759. [ABSTRACT FROM AUTHOR]

The orbicularis oculi are the sphincter muscles of the eyelids and are involved in modulating facial expression. They differ from both limb and extraocular muscles (EOMs) in their histology and biochemistry. Weakness of the orbicularis oculi muscles is a feature of neuromuscular disorders affecting the neuromuscular junction, and weakness of facial muscles and ptosis have also been described in patients with mutations in the ryanodine receptor gene. Here, we investigate human orbicularis oculi muscles and find that they are functionally more similar to quadriceps than to EOMs in terms of excitation-contraction coupling components. In particular, they do not express the cardiac isoform of the dihydropyridine receptor, which we find to be highly expressed in EOMs where it is likely responsible for the large depolarization-induced calcium influx. We further show that human orbicularis oculi and EOMs express high levels of utrophin and low levels of dystrophin, whereas quadriceps express dystrophin and low levels of utrophin. The results of this study highlight the notion that myotubes obtained by explanting satellite cells from different muscles are not functionally identical and retain the physiological characteristics of their muscle of origin. Furthermore, our results indicate that sparing of facial and EOMs in patients with Duchenne muscular dystrophy is the result of the higher levels of utrophin expression. [ABSTRACT FROM AUTHOR]

Calcium is an ubiquitous second messenger mediating numerous physiological processes, including muscle contraction and neuronal excitability. Ca2+ is stored in the ER/SR and is released into the cytoplasm via the opening of intracellular inositol trisphosphate receptor and ryanodine receptor calcium channels. Whereas in skeletal muscle, isoform 1 of the RYR is the main channel mediating calcium release from the SR leading to muscle contraction, the function of ubiquitously expressed ryanodine receptor 3 (RYR3) is far from clear; it is not known whether RYR3 plays a role in excitation-contraction coupling. We recently reported that human extraocular muscles express high levels of RYR3, suggesting that such muscles may be useful to study the function of this isoform of the Ca2+ channel. In the present investigation, we characterize the visual function of ryr3-/- mice. We observe that ablation of RYR3 affects both mechanical properties and calcium homeostasis in extraocular muscles. These changes significantly impact vision. Our results reveal for the first time an important role for RYR3 in extraocular muscle function. [ABSTRACT FROM AUTHOR]