In Aging, researchers have reported on how an increase in FGF21, a myokine that encourages muscle growth, impacts the progression of amyotrophic lateral sclerosis (ALS).
Progressive and fatal
ALS is an age-related disease that is characterized by the degeneration of motor neurons throughout the spinal cord and in the brain, leading to death by respiratory failure three to five years after onset [1]. Last year, the authors of this study conducted a review concluding that the earliest stages of ALS can be detected in skeletal muscle [2], and other work has found evidence that the disease progresses from the muscles to the brain, not the other way around [3].
Identifying the key factors behind this progression, however, remains an uncompleted task. The transcriptome, which represens RNA gene expression, is heavily dysregulated in ALS patients [2]. Which signals represent the disease, and which signals represent a cellular attempt to mitigate the disease, however, remains an open question [4], one that has been investigated for nearly a decade [5].
For example, one of these biomarkers is FGF21, which this research team had previously investigated in this context [6]. Here, they redoubled their efforts in an effort to determine FGF21’s role in ALS and how it may impact the disease.
FGF21 is co-located with atrophied fibers
This study was carried out using muscle biopsies from patients gleaned at this team’s ALS clinic. Like the broader population, they found this disease to be more common in males than females, and the average age of patients was approximately 57.
Compared to biopsies of normal tissue, the FGF21 expression in the muscle of most, but not all, ALS patients was highly elevated as measured by an mRNA analysis. In the spinal cord, some ALS patients had levels below the norm, but others had extraordinarily high levels. While most patients that had high FGF21 in the spinal cord also had high levels in muscle, there were exceptions.
These patterns were mimicked in model mice that express a mutant version (G93A) of a particular antioxidant gene, SOD1, in skeletal muscle. These short-lived mice had much higher levels of FGF21 in both muscle tissue and spinal cord than their unmodified counterparts. While much of this came from the liver, even more originated from the muscle itself.
ALS does not cause every muscle fiber to suffer the same level of atrophy at once; rather, both atrophied and unatrophied fibers can be found within the same biopsy. In human muscle tissue, FGF21 and ALS were found to be co-located; atrophied fibers were found to have much more FGF21 than unatrophied ones.
FGF21 mitigates, not accelerates
An increase in FGF21 in blood plasma was associated with a slower progression and increased survival. Patients with low circulating FGF21 were likely to survive for only 18 months, while patients with high levels survived for an average of 75. Interestingly, a high BMI was associated with greater FGF21.
KLB is the gene that encodes β-Klotho, a co-receptor of FGF21. Its levels varied wildly in ALS patients; before the patients’ deaths, they expressed four times as much KLB as the control group, but a post-mortem examination showed that they expressed only half as much as controls, a finding that was recapitulated in G93A model mice.
Using iPSC technology to generate motor neurons from ALS patients, these findings were recapitulated in nervous tissue as well. Compared to controls, ALS motor neurons had half as much FGF21 but thrice as much KLB, a finding that appeared to be related to the effects of oxidative stress.
ALS-affected cells are much more vulnerable to oxidative stress than unaffected cells. Relatively low levels of hydrogen peroxide, which do not kill most of the control group, killed the majority of ALS motor neurons. Administering FGF21 to these cells increased their viability, although not quite to the level of controls.
FGF21 is myogenic; under normal circumstances, it generates functional tissue and increases strength. These researchers found that it indeed decreases stress in muscle tissue while increasing the number of muscle cells.
In total, the upregulation of FGF21 in ALS appears to be an attempt to mitigate the atrophy and cellular stress that characterize the disease. However, the researchers point to a problem with the FGF21-KLB axis and suggest that this dysfunction is key to the progression of ALS. Further work needs to be done to analyze this axis and determine if and how it can be effectively targeted to stop this deadly disease.
Literature
[1] Hardiman, O., Van Den Berg, L. H., & Kiernan, M. C. (2011). Clinical diagnosis and management of amyotrophic lateral sclerosis. Nature reviews neurology, 7(11), 639-649.
[2] King, P. H. (2024). Skeletal muscle as a molecular and cellular biomarker of disease progression in amyotrophic lateral sclerosis: a narrative review. Neural Regeneration Research, 19(4), 747-753.
[3] Moloney, E. B., de Winter, F., & Verhaagen, J. (2014). ALS as a distal axonopathy: molecular mechanisms affecting neuromuscular junction stability in the presymptomatic stages of the disease. Frontiers in neuroscience, 8, 252.
[4] Verma, S., Khurana, S., Vats, A., Sahu, B., Ganguly, N. K., Chakraborti, P., … & Taneja, V. (2022). Neuromuscular junction dysfunction in amyotrophic lateral sclerosis. Molecular neurobiology, 59(3), 1502-1527.
[5] Benatar, M., Boylan, K., Jeromin, A., Rutkove, S. B., Berry, J., Atassi, N., & Bruijn, L. (2016). ALS biomarkers for therapy development: state of the field and future directions. Muscle & nerve, 53(2), 169-182.
[6] Si, Y., Cui, X., Crossman, D. K., Hao, J., Kazamel, M., Kwon, Y., & King, P. H. (2018). Muscle microRNA signatures as biomarkers of disease progression in amyotrophic lateral sclerosis. Neurobiology of disease, 114, 85-94.
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