Taurine Depletion Causes ipRGC Loss and Increases Light-Induced Photoreceptor Degeneration.

Purpose: To examine if light exposure exacerbates retinal neuronal loss induced by taurine depletion. Methods: Albino rats received ß-alanine in the drinking water to induce taurine depletion. One month later, half of the animals were exposed to white light (3000 lux) continuously for 48 hours and the rest remained in normal environmental conditions. A control group of animals nontreated with ß-alanine also was prepared, and half of them were exposed to light using the same protocol. All the animals were processed 2 months after the beginning of the experiment. Retinas were dissected as wholemounts and immunodetected with antibodies against Brn3a, melanopsin, S-opsin, and L-opsin to label different retinal populations: Brn3a+ retinal ganglion cells (RGCs) (image-forming RGCs), m+RGCs (non-image-forming RGCs), and S- and L/M-cones, respectively. Results: Light exposure did not affect the numbers of Brn3a+RGCs or m+RGCs but diminished the numbers of S- and L/M-cones and caused the appearance of rings devoid of cones, mainly in an "arciform" area in the superotemporal retina. Taurine depletion caused a diminution of all the studied populations, with m+RGCs the most affected, followed by S-cones. Light exposure under taurine depletion increased photoreceptor degeneration but did not seem to increase Brn3a+RGCs or m+RGCs loss. Conclusions: Our results document that taurine is necessary for cell survival in the rat retina and even more under light-induced photoreceptor degeneration. Thus, taurine supplementation may help to prevent retinal degenerations, especially those that commence with S-cone degeneration or in which light may be an etiologic factor, such as inherited retinal degenerations, AMD, or glaucoma.

Taurine Promotes Retinal Ganglion Cell Survival Through GABAB Receptor Activation.

Retinal ganglion cell (RGC) degeneration occurs in numerous retinal diseases, either as a primary process like in glaucoma, or secondary to photoreceptor loss and no efficient compound targeting directly RGC neuroprotection is yet available. We previously described that taurine exerts a direct protective effect on RGCs cultured under serum-deprived conditions. Because taurine was known to have an agonist-like activity for GABA/glycine receptors, we investigated here if the taurine-elicited neuroprotective effect may be mediated through the activation of these receptors using selective antagonist ligands. RGCs were purified, seeded in 96-well plate and maintained in culture during 6 days in vitro. Viable cells were labelled with calcein and densities in full-well area were then automatically counted. Here we show that the protective effect of taurine against RGC loss observed under serum deprivation can be mediated through the GABAB receptor stimulation. Hence, two selective agonists, including baclofen, at this metabotropic GABAB receptor were found to reproduce taurine action by enhancing RGC survival in culture. This study suggests that GABAB receptor stimulation provides direct neuroprotection for RGCs. Accordingly, drugs targeting GABAB receptor may represent a new way for the prevention of RGC degeneration.

Quantitative and Topographical Analysis of the Losses of Cone Photoreceptors and Retinal Ganglion Cells Under Taurine Depletion.

PURPOSE: Taurine depletion is known to induce photoreceptor degeneration and was recently found to also trigger retinal ganglion cell (RGC) loss similar to the retinal toxicity of vigabatrin. Our objective was to study the topographical loss of RGCs and cone photoreceptors, with a distinction between the two cone types (S- and L- cones) in an animal model of induced taurine depletion. METHODS: We used the taurine transporter (Tau-T) inhibitor, guanidoethane sulfonate (GES), to induce taurine depletion at a concentration of 1% in the drinking water. Spectral-domain optical coherence tomography (SD-OCT) and electroretinograms (ERG) were performed on animals after 2 months of GES treatment administered through the drinking water. Retinas were dissected as wholemounts and immunodetection of Brn3a (RGC), S-opsin (S-cones), and L-opsin (L-cones) was performed. The number of Brn3a+ RGCs, and L- and S-opsin+ cones was automatically quantified and their retinal distribution studied using isodensity maps. RESULTS: The treatment resulted in a significant reduction in plasma taurine levels and a profound dysfunction of visual performance as shown by ERG recordings. Optical coherence tomography analysis revealed that the retina was thinner in the taurine-depleted group. S-opsin+cones were more affected (36%) than L-opsin+cones (27%) with greater cone cell loss in the dorsal area whereas RGC loss (12%) was uniformly distributed. CONCLUSIONS: This study confirms that taurine depletion causes RGC and cone loss. Electroretinograms results show that taurine depletion induces retinal dysfunction in photoreceptors and in the inner retina. It establishes a gradient of cell loss depending on the cell type from S-opsin+cones, L-opsin+cones, to RGCs. The greater cell loss in the dorsal retina and of the S-cone population may underline different cellular mechanisms of cellular degeneration and suggests that S-cones may be more sensitive to light-induced retinal toxicity enhanced by the taurine depletion.

Advances in the understanding of skeletal muscle weakness in murine models of diseases affecting nerve-evoked muscle activity, motor neurons, synapses and myofibers.

Disease processes and trauma affecting nerve-evoked muscle activity, motor neurons, synapses and myofibers cause different levels of muscle weakness, i.e., reduced maximal force production in response to voluntary activation or nerve stimulation. However, the mechanisms of muscle weakness are not well known. Using murine models of amyotrophic lateral sclerosis (SOD1(G93A) transgenic mice), congenital myasthenic syndrome (AChE knockout mice and Musk(V789M/-) mutant mice), Schwartz-Jampel syndrome (Hspg2(C1532YNEO/C1532YNEO) mutant mice) and traumatic nerve injury (Neurotomized wild-type mice), we show that the reduced maximal activation capacity (the ability of the nerve to maximally activate the muscle) explains 52%, 58% and 100% of severe weakness in respectively SOD1(G93A), Neurotomized and Musk mice, whereas muscle atrophy only explains 37%, 27% and 0%. We also demonstrate that the impaired maximal activation capacity observed in SOD1, Neurotomized, and Musk mice is not highly related to Hdac4 gene upregulation. Moreover, in SOD1 and Neurotomized mice our results suggest LC3, Fn14, Bcl3 and Gadd45a as candidate genes involved in the maintenance of the severe atrophic state. In conclusion, our study indicates that muscle weakness can result from the triggering of different signaling pathways. This knowledge may be helpful in designing therapeutic strategies and finding new drug targets for amyotrophic lateral sclerosis, congenital myasthenic syndrome, Schwartz-Jampel syndrome and nerve injury.

Impaired adaptive response to mechanical overloading in dystrophic skeletal muscle.

Dystrophin contributes to force transmission and has a protein-scaffolding role for a variety of signaling complexes in skeletal muscle. In the present study, we tested the hypothesis that the muscle adaptive response following mechanical overloading (ML) would be decreased in MDX dystrophic muscle lacking dystrophin. We found that the gains in muscle maximal force production and fatigue resistance in response to ML were both reduced in MDX mice as compared to healthy mice. MDX muscle also exhibited decreased cellular and molecular muscle remodeling (hypertrophy and promotion of slower/oxidative fiber type) in response to ML, and altered intracellular signalings involved in muscle growth and maintenance (mTOR, myostatin, follistatin, AMPKα1, REDD1, atrogin-1, Bnip3). Moreover, dystrophin rescue via exon skipping restored the adaptive response to ML. Therefore our results demonstrate that the adaptive response in response to ML is impaired in dystrophic MDX muscle, most likely because of the dystrophin crucial role.

Effect of locomotor training on muscle performance in the context of nerve-muscle communication dysfunction.

INTRODUCTION: The effects of locomotor training (LT) on skeletal muscle after peripheral nerve injury and acetylcholinesterase deficiency are not well documented. METHODS: We determined the effects of LT on mouse soleus muscle performance after sciatic nerve transection with excision (full and permanent denervation), nerve transection (partial functional reinnervation), nerve crush (full denervation with full functional reinnervation), and acetylcholinesterase deficiency (alteration in neuromuscular junction functioning). RESULTS: We found no significant effect of LT on the recovery of soleus muscle weight, maximal force in response to muscle stimulation, and fatigue resistance after nerve transection with or without excision. However, LT significantly increased soleus muscle fatigue resistance after nerve crush and acetylcholinesterase deficiency. Moreover, hindlimb immobilization significantly aggravated the deficit in soleus muscle maximal force production and atrophy after nerve crush. CONCLUSIONS: LT is beneficial, and reduced muscle use is detrimental for intrinsic muscle performance in the context of disturbed nerve-muscle communication.