Accumulation of formaldehyde causes motor deficits in an in vivo model of hindlimb unloading

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.

Acute high‐altitude hypoxia exposure causes neurological deficits via formaldehyde accumulation

“…Administration with CoQ10 could also prevent the decline of ALDH2 expression (HH vs. HH + CoQ10, p = 0.0054) (Figure 3F) and activity (HH vs. HH + CoQ10, p < 0.0001) (Figure 3G) under hypobaric hypoxic conditions. These findings indicated that CoQ10 can prevent FA accumulation not only by combination with FA, 14,25 but also by preserving its normal metabolism.…”

“…Excessive cerebral FA shows critically detrimental effect on the nervous system, while CoQ10 administration is useful in multiple neurological diseases 45 . It can directly combine with the FA molecule for elimination and function preservation 14,25 . It can also inhibit ALDH2 inactivation to promote clearance 46 .…”

“…45 It can directly combine with the FA molecule for elimination and function preservation. 14,25 It can also inhibit ALDH2 inactivation to promote clearance. 46 48,49 oxidative stress, 50 excessive mitophagy and neuroinflammation, 51 may also impair neurological function in hypoxia conditions and need to be further explored.…”

“…Our previous studies have found that CoQ10 can combine with FA for elimination. 14,25 Whether administration with CoQ10 before hypoxia exposure could prevent FA accumulation is still not clear. Therefore, we treated the mice with CoQ10 for 3 days before acute hypobaric hypoxia exposure and found that the levels of FA in the cerebrum were significantly reduced (HH vs. HH + CoQ10, p < 0.0001) (Figure 3A,B).…”

Influence of formaldehyde exposure on the molecules of the NO/cGMP-cAMP signaling pathway in different brain regions of Balb/c mice

“…Despite its low level in the body, FA plays a crucial role in metabolic processes (Ye et al, 2013; Tang et al, 2013). Elevated levels of FA in the body can cause damage to critical systems, particularly the central nervous system, leading to difficulties in learning and memory impairment (Yao et al, 2021). Studies conducted on animals have shown that exposure to FA can result in significant deterioration in learning ability and memory, as well as morphological changes in rat hippocampal tissue (Li et al, 2020; Wei et al, 2022; Songur et al, 2003).…”