Enhanced axonal response of mitochondria to demyelination offers neuroprotection:implications for multiple sclerosis

Axonal loss is the key pathological substrate of neurological disability in demyelinating disorders, including multiple sclerosis (MS). However, the consequences of demyelination on neuronal and axonal biology are poorly understood. The abundance of mitochondria in demyelinated axons in MS raises the possibility that increased mitochondrial content serves as a compensatory response to demyelination. Here, we show that upon demyelination mitochondria move from the neuronal cell body to the demyelinated axon, increasing axonal mitochondrial content, which we term the axonal response of mitochondria to demyelination (ARMD). However, following demyelination axons degenerate before the homeostatic ARMD reaches its peak. Enhancement of ARMD, by targeting mitochondrial biogenesis and mitochondrial transport from the cell body to axon, protects acutely demyelinated axons from degeneration. To determine the relevance of ARMD to disease state, we examined MS autopsy tissue and found a positive correlation between mitochondrial content in demyelinated dorsal column axons and cytochrome c oxidase (complex IV) deficiency in dorsal root ganglia (DRG) neuronal cell bodies. We experimentally demyelinated DRG neuron-specific complex IV deficient mice, as established disease models do not recapitulate complex IV deficiency in neurons, and found that these mice are able to demonstrate ARMD, despite the mitochondrial perturbation. Enhancement of mitochondrial dynamics in complex IV deficient neurons protects the axon upon demyelination. Consequently, increased mobilisation of mitochondria from the neuronal cell body to the axon is a novel neuroprotective strategy for the vulnerable, acutely demyelinated axon. We propose that promoting ARMD is likely to be a crucial preceding step for implementing potential regenerative strategies for demyelinating disorders.</p

Divergent genotypes for fatness or residual feed intake in Angus cattle. 7. Low-fat and low-RFI cows produce more liveweight and better gross margins than do high-fat and high-RFI cows when managed under the same conditions

The present paper focuses on the economic evaluation of the observed differences in maternal productivity of different genetic lines in Angus cattle that were managed under contrasting nutritional regimes typical of southern Australia. Five hundred Angus cows were managed concurrently at two locations in southern Australia. On each site, the cows were managed under the following two different nutritional treatments: High and Low, to simulate different stocking rates. Cows selected for a divergence in either carcass rib-fat depth or residual feed intake based on mid-parent estimated breeding values for those traits, were allocated in replicate groups to either High- or Low-nutrition treatments. By design, the supplementary feeding regime was the same for the High and Low genetic lines to ensure genetic differences were not confounded with management differences. Animal productivity results from the experiment were used as input data to evaluate the economic performance of the four genetic lines under the two nutritional treatments. Two methods were used; the first was a gross-margin calculation of income minus variable costs as AU$ per breeding cow for a 1000-cow herd; the second was a whole-farm linear programming model maximising the gross margin. Stocking rates were optimised by matching the energy requirements for the whole herd with the energy available from pasture and supplementary feed on a representative 700-ha farm. Using the two methods of calculating gross margin (per cow and optimised per hectare), including examination of sensitivity to changes in prices of cattle and supplementary feed, the present study demonstrated that genetically leaner cows due to selection of low fat or low residual feed intake, had gross margins superior to those of genetically fatter cows. They generated more income by selling more liveweight due to heavier weights and higher stocking rates. The results are affected by the management system utilised and some confounding with growth (leaner genetic lines had higher growth estimated breeding values), but will assist producers to make more informed decisions about how to manage animal breeding and nutritional interactions