Lack of movement in neurological diseases : effects on neurogenesis and muscle-nerve interaction

Both astronauts and patients affected by chronic movement-limiting pathologies such as spinal muscular atrophy, spinal cord injury, multiple sclerosis and others, face impairment in muscle and/or brain performance. Since life support increases their survival expectations and since in the (quite near) future astronauts might well stay in space for very long periods of time, both of these groups are likely to be subjected to the effects of the prolonged motor deprivation that can influence not only the motor or metabolic systems but also, the nervous system, altering neurogenesis and the interaction between motoneurons and muscle cells.Four-month-old male C57BL/6 mice were randomly selected and assigned to control (CTR) or Hind limb Unloading [1] (HU) groups. The HU (suspension) last 14 days; CTR animals were kept in similar cages and conditions, but they were free to move without restraint, for an equivalent period. At the end of the suspension period, animals were sacrificed, limb skeletal muscle (gastrocnemious and soleus) and brain dissected and processed for the appropriate experimental procedures. From our in vitro analysis we determined that Neural Stem Cells (NSCs) derived from the SVZ obtained from HU mice show a lower proliferation capability compared to CTR (unrestrained) mice with a doubling time that is almost 4 times that observed in the CTR. These results are in agreement with a cytofluorimetric analysis of the cell cycle which indicates that the HU-derived NSCs have a block in G0/G1 together with a shortening of the S and G2/M phases. In addition, in NSCs obtained from movement-restrained animals, the differentiation is altered, with a significant reduction of the number of β-Tubulin III positive cells and a co-expression of Glial Fibrillary Acidic Protein, that suggests an incomplete differentiation/maturation of the NSCs which, most likely, do not reach mature neuronal electrical membrane properties. Cellular metabolism mostly occurs in mitochondrial organelles and the number of viable cells depends on the mitochondrial membrane and the respiratory chain. From our preliminary data, NSCs obtained from HU mice have a lower mitochondrial activity with respect to the CTR NSCs as measured by a MTT assay. Little information is available about the effect of prolonged muscle disuse on neurogenesis. Most of the available data describe in vivo changes with little focus on the proliferation/differentiation process [2], whereas an in vitro study of NSCs characteristics, including gene expression and response to trophic factors, is lacking. These results might reflect a profound and lasting change in growth factors and neurotrophins signalling and confirm the deleterious effects of inactivity strengthening the neuroprotective function of physical exercise. Overall, these data lead us to believe the existence of a possible link between exercise/muscle disuse, metabolism and neurotrophic factors in the brain. 1. Desaphy, J.F., et al., 2005 Neurobiol Dis, 18: 356-65. 2. Yasuhara, T., et al., 2007 Neuroscience, 149: 182-91.