Fndc5, also known as fibronectin type III domain-containing protein 5, codes for a transmembrane protein. Upon cleavage, it releases irisin, a myokine. Fndc5 is associated with multiple biological processes. It is involved in the PGC-1α/FNDC5 pathway, which links endurance exercise to the expression of brain-derived neurotrophic factor (BDNF) in the brain [2]. It also plays a role in maintaining metabolic homeostasis, and its dysregulation can lead to systemic metabolism imbalance [5]. Gene knockout mouse models have been valuable in studying Fndc5's functions.

In AD models, knockdown of brain Fndc5/irisin impairs long-term potentiation and novel object recognition memory in mice, while boosting its levels rescues synaptic plasticity and memory. Blockade of either peripheral or brain Fndc5/irisin attenuates the neuroprotective actions of physical exercise on synaptic plasticity and memory in AD mice, indicating its role as a mediator of exercise-induced benefits in AD [1]. In doxorubicin-induced cardiotoxicity, Fndc5 deficiency results in increased oxidative damage and apoptosis in H9C2 cells, while Fndc5 overexpression or irisin treatment alleviates these effects [3]. In intervertebral disc degeneration (IVDD), knocking out Fndc5 compromises the beneficial effects of physical exercise, while overexpression of Fndc5 in NP tissue alleviates IVD degeneration [4]. In traumatic brain injury (TBI) mouse models, knockout of Fndc5 increases the lesion volume and exacerbates apoptosis and neurological deficits, while Fndc5 overexpression has a neuroprotective effect [6].

In conclusion, Fndc5, through its cleavage product irisin, plays crucial roles in multiple biological processes. Model-based research, especially using Fndc5 knockout mouse models, has revealed its significance in diseases such as Alzheimer's disease, doxorubicin-induced cardiotoxicity, IVDD, and TBI. These findings highlight Fndc5 as a potential therapeutic target for these conditions.

References:

1. Lourenco, Mychael V, Frozza, Rudimar L, de Freitas, Guilherme B, Ferreira, Sergio T, De Felice, Fernanda G. 2019. Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer's models. In Nature medicine, 25, 165-175. doi:10.1038/s41591-018-0275-4. https://pubmed.ncbi.nlm.nih.gov/30617325/

2. Wrann, Christiane D, White, James P, Salogiannnis, John, Greenberg, Michael E, Spiegelman, Bruce M. 2013. Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. In Cell metabolism, 18, 649-59. doi:10.1016/j.cmet.2013.09.008. https://pubmed.ncbi.nlm.nih.gov/24120943/

3. Zhang, Xin, Hu, Can, Kong, Chun-Yan, Ma, Zhen-Guo, Tang, Qi-Zhu. 2019. FNDC5 alleviates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via activating AKT. In Cell death and differentiation, 27, 540-555. doi:10.1038/s41418-019-0372-z. https://pubmed.ncbi.nlm.nih.gov/31209361/

4. Zhou, Wenxian, Shi, Yifeng, Wang, Hui, Zhang, Xiaolei, Wu, Aimin. 2022. Exercise-induced FNDC5/irisin protects nucleus pulposus cells against senescence and apoptosis by activating autophagy. In Experimental & molecular medicine, 54, 1038-1048. doi:10.1038/s12276-022-00811-2. https://pubmed.ncbi.nlm.nih.gov/35882943/

5. Cao, Richard Y, Zheng, Hongchao, Redfearn, Damian, Yang, Jian. 2019. FNDC5: A novel player in metabolism and metabolic syndrome. In Biochimie, 158, 111-116. doi:10.1016/j.biochi.2019.01.001. https://pubmed.ncbi.nlm.nih.gov/30611879/

6. Ge, Yufeng, Wu, Xun, Cai, Yaning, Qu, Yan, Ge, Shunnan. 2024. FNDC5 prevents oxidative stress and neuronal apoptosis after traumatic brain injury through SIRT3-dependent regulation of mitochondrial quality control. In Cell death & disease, 15, 364. doi:10.1038/s41419-024-06748-w. https://pubmed.ncbi.nlm.nih.gov/38802337/