
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.09.11.611693
preprint
1
Article
The myokine FGF21 associates with enhanced survival in ALS and mitigates stress-induced cytotoxicity
Guha Abhishek http://orcid.org/0000-0003-2767-9941

Si Ying
Smith Reed
Kazamel Mohamed
Jiang Nan
Smith Katherine A.
Thalacker-Mercer Anna http://orcid.org/0000-0002-9124-7927

Singh Brijesh K.
Ho Ritchie http://orcid.org/0000-0003-1496-4436

Andrabi Shaida A
Silva Pereira Joao D Tavares Da
Salgado Juliana S.
Agrawal Manasi
Velic Emina Horvat
King Peter H. http://orcid.org/0000-0001-9391-7464

14 9 2024
2024.09.11.611693https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.09.11.611693
nihpp-2024.09.11.611693.pdf
Abstract

Amyotrophic lateral sclerosis (ALS) is an age-related and fatal neurodegenerative disease characterized by progressive muscle weakness. There is marked heterogeneity in clinical presentation, progression, and pathophysiology with only modest treatments to slow disease progression. Molecular markers that provide insight into this heterogeneity are crucial for clinical management and identification of new therapeutic targets. In a prior muscle miRNA sequencing investigation, we identified altered FGF pathways in ALS muscle, leading us to investigate FGF21. We analyzed human ALS muscle biopsy samples and found a large increase in FGF21 expression with localization to atrophic myofibers and surrounding endomysium. A concomitant increase in FGF21 was detected in ALS spinal cords which correlated with muscle levels. FGF21 was increased in the SOD1 G93A mouse beginning in presymptomatic stages. In parallel, there was dysregulation of the co-receptor, β-Klotho. Plasma FGF21 levels were increased and high levels correlated with slower disease progression, prolonged survival, and increased body mass index. In NSC-34 motor neurons and C2C12 muscle cells expressing SOD1 G93A or exposed to oxidative stress, ectopic FGF21 mitigated loss of cell viability. In summary, FGF21 is a novel biomarker in ALS that correlates with slower disease progression and exerts trophic effects under conditions of cellular stress.
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pmc
