Mechanism of Fat Mass and Obesity-Related Gene-Mediated Heme Oxygenase-1 m6A Modification in the Recovery of Neurological Function in Mice with Spinal Cord Injury

Objectives: This study examined the mechanism of fat mass and obesity-related gene (FTO)-mediated heme oxygenase-1 (HO-1) m6A modification facilitating neurological recovery in spinal cord injury (SCI) mice. FTO/HO-1 was identified as a key regulator of SCI as well as a potential target for treatment of SCI.

Methods: An SCI mouse was treated with pcDNA3.1-FTO/pcDNA3.1-NC/Dac51. An oxygen/glucose deprivation (OGD) cell model simulated SCI, with cells treated with pcDNA3.1-FTO/si-HO-1/Dac51. Motor function and neurobehavioral evaluation were assessed using the Basso, Beattie, and Bresnahan (BBB) scale and modified neurological severity score (mNSS). Spinal cord pathology and neuronal Apoptosis were assessed. Further, FTO/HO-1 mRNA and protein levels, HO-1 mRNA stability, the interaction of YTHDF2 with HO-1 mRNA, neuronal viability/Apoptosis, and HO-1 m6A modification were evaluated.

Results: Spinal cord injury mice exhibited reduced BBB, elevated mNSS scores, disorganized spinal cord cells, scattered nuclei, and severe nucleus pyknosis. pcDNA3.1-FTO elevated FTO mRNA, protein expression, and BBB score; reduced the mNSS score of SCI mice; decreased neuronal apoptosis; improved the cell arrangement; and improved nucleus pyknosis in spinal cord tissues. OGD decreased FTO expression. FTO upregulation ameliorated OGD-induced neuronal Apoptosis. pcDNA3.1-FTO reduced HO-1 mRNA and protein and HO-1 m6A modification, while increasing HO-1 mRNA stability and FTO in OGD-treated cells. FTO upregulated HO-1 by modulating m6A modification. HO-1 downregulation attenuated the effect of FTO. pcDNA3.1-FTO/Dac51 increased the HO-1 m6A level in mouse spinal cord tissue homogenate, reduced BBB, boosted mNSS scores of SCI mice, aggravated nucleus pyknosis, and increased neuronal Apoptosis in spinal cord tissues, confirming that FTO mediated HO-1 m6A modification facilitated neurological recovery in SCI mice.

Conclusion: The fat mass and obesity-related gene modulates HO-1 mRNA stability by regulating m6A modification levels, thereby influencing HO-1 expression and promoting neurological recovery in SCI mice.

Fat mass and obesity‐related genes; HO‐1; Neuron; Spinal cord injury; m6A.