Abstract
During duration spaceflight, or after their return to earth, astronauts have often suffered from gait instability and cerebellar ataxia. Here, we use a mouse model of hindlimb unloading (HU) to explore a mechanism of how reduced hindlimb burden may contribute to motor deficits. The results showed that these mice which have experienced HU for 2 weeks exhibit a rapid accumulation of formaldehyde in the gastrocnemius muscle and fastigial nucleus of cerebellum. The activation of semicarbazide-sensitive amine oxidase and sarcosine dehydrogenase induced by HU-stress contributed to formaldehyde generation and loss of the abilities to maintain balance and coordinate motor activities. Further, knockout of formaldehyde dehydrogenase (FDH-/-) in mice caused formaldehyde accumulation in the muscle and cerebellum that was associated with motor deficits. Remarkably, formaldehyde injection into the gastrocnemius muscle led to gait instability; especially, microinfusion of formaldehyde into the fastigial nucleus directly induced the same symptoms as HU-induced acute ataxia. Hence, excessive formaldehyde damages motor functions of the muscle and cerebellum.
Highlights
During duration spaceflight, or after their return to earth, astronauts have often suffered from gait instability and cerebellar ataxia
The findings showed that hindlimb unloading (HU)-stress promotes formaldehyde generation by activating these formaldehydegenerating enzymes, and inhibits formaldehyde degradation by reducing the expression and activity of formaldehyde dehydrogenase (FDH, named alcohol dehydrogenase-5 (ADH5) or Aldh1l1)
The results showed that cerebellar formaldehyde levels in the model group on day 14 were elevated 3-fold compared to the control group (Fig. 1d)
Summary
After their return to earth, astronauts have often suffered from gait instability and cerebellar ataxia. In a rat model of hindlimb unloading (HU, a model of partially simulated microgravity stress), muscle atrophy in the hind limbs had recovered after a 2-week recovery period, the locomotor deficits were not reversed[9,10]. These data strongly suggest that a cerebellum impaired by microgravity may be a direct and critical factor in the cerebellar ataxia experienced by astronauts. We investigated whether HU-stress induces formaldehyde accumulation in the muscle and cerebellum and leads to motor disorders including: gait instability and cerebellar ataxia. The combination with 630-nm red light and nano-packed coenzyme Q10 has a better therapeutic effect in degrading systemic formaldehyde and restoring motor functions than single treatment
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