Fndc5, encoding a transmembrane protein, is well-known for its role in generating the myokine irisin upon cleavage. It is expressed in tissues like skeletal muscle, heart, and brain [3]. FNDC5 is associated with multiple pathways, such as the PGC-1α/FNDC5 pathway which links endurance exercise to BDNF expression in the brain [2]. It also plays a crucial role in maintaining metabolic homeostasis and is involved in various biological processes related to metabolism, synapse function, and cell survival [7]. Genetically modified mouse models, like global or tissue-specific Fndc5 knockout mice, have been valuable in studying its functions [3].

In AD models, knockdown of brain Fndc5/irisin impairs long-term potentiation and memory, while boosting its levels rescues synaptic plasticity and memory. Also, blockade of either peripheral or brain Fndc5/irisin attenuates the neuroprotective effects of exercise, indicating it is a key mediator of exercise-induced benefits in AD [1]. In doxorubicin-induced cardiotoxicity, Fndc5 deficiency increases oxidative damage and apoptosis in H9C2 cells, while its overexpression or irisin treatment alleviates these effects, acting through the AKT/mTOR and AKT/GSK3β/FYN/Nrf2 axes [4]. In intervertebral disc degeneration, knocking out Fndc5 compromises the beneficial effects of physical exercise, which otherwise increases Fndc5/irisin levels, reduces senescence and apoptosis, and activates autophagy in nucleus pulposus cells [5]. In non-alcoholic fatty liver disease, NR-induced elevation of Fndc5/irisin levels is crucial for the therapeutic effects of NR, as these effects are compromised in Fndc5-/-mice [6]. In traumatic brain injury, knockout of Fndc5 increases lesion volume, exacerbates apoptosis and neurological deficits, while its overexpression has a neuroprotective effect [8].

In conclusion, Fndc5 plays essential roles in multiple biological processes. Through gene knockout mouse models, its significance in diseases such as Alzheimer's disease, doxorubicin-induced cardiotoxicity, intervertebral disc degeneration, non-alcoholic fatty liver disease, and traumatic brain injury has been revealed. 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. Maak, Steffen, Norheim, Frode, Drevon, Christian A, Erickson, Harold P. . Progress and Challenges in the Biology of FNDC5 and Irisin. In Endocrine reviews, 42, 436-456. doi:10.1210/endrev/bnab003. https://pubmed.ncbi.nlm.nih.gov/33493316/

4. 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/

5. 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/

6. Li, Dong-Jie, Sun, Si-Jia, Fu, Jiang-Tao, Shen, Fu-Ming, Wang, Pei. 2021. NAD+-boosting therapy alleviates nonalcoholic fatty liver disease via stimulating a novel exerkine Fndc5/irisin. In Theranostics, 11, 4381-4402. doi:10.7150/thno.53652. https://pubmed.ncbi.nlm.nih.gov/33754067/

7. 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/

8. 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/