Targeting FGF21 hormone may slow ALS disease progression
Higher blood levels tied to longer survival
FGF21, a hormone that helps cells regulate energy use and respond to stress, may protect muscles and nerve cells from damage related to amyotrophic lateral sclerosis (ALS), slowing disease progression.
A study found ALS patients had significantly higher levels of FGF21 in their blood and muscles than healthy controls, with higher blood FGF21 levels correlating with prolonged survival. Exposure to FGF21 allowed cells to survive stressful conditions.
“Taken together, these findings identify FGF21 as a biomarker that provides insight into … ALS while at the same time identifying it as a potential target for future therapeutic development,” the team wrote.
The study, “The myokine FGF21 associates with enhanced survival in ALS and mitigates stress-induced cytotoxicity,” was published in Aging.
ALS is caused when motor neurons — the nerve cells that help control voluntary movement — become damaged and eventually die. As the disease progresses and more cells are affected, muscle cells waste away.
Molecular markers ‘crucial’ in identifying targets for treatment
Movement-related symptoms are characteristic of ALS. However, the clinical presentation and the rate of motor decline can vary substantially among individuals. “Molecular markers that provide insight into this heterogeneity [variability] are crucial for clinical management and identification of new therapeutic targets,” the researchers wrote.
The team previously identified potential alterations in signaling pathways involving FGF21. In the latest study, they investigated these alterations in greater detail.
The researchers tested the activity of FGF21, the gene that codes for FGF21, in muscle samples from people with ALS and controls. On average, ALS participants had approximately eight times more FGF21 activity than control participants, although this varied considerably among ALS patients.
A mouse model of ALS also confirmed the results, with differences in gene activity beginning before motor symptoms.
Microscopic analysis of the human ALS muscle samples revealed that FGF21 concentrations were highest in atrophic (wasting) muscle fibers and the surrounding tissue. Samples representing more advanced (end-stage) disease showed that FGF21 activity was much higher (63 times) in patients than in controls, “indicating that FGF21 expression [activity] in muscle increases with disease progression,” the investigators wrote. A simultaneous increase in FGF21 was detected in the spinal cord, which correlated with muscle levels.
The researchers then examined FGF21 levels in plasma, the liquid component of blood. Although the difference was less pronounced than in muscle samples, FGF21 was still significantly higher in ALS participants than in controls.
To investigate the potential utility of this blood biomarker, they compared survival rates in a subset of 16 participants. Those whose plasma FGF21 level was less than 1.5 times higher than that of control participants survived a median of 18 months (1.5 years) after diagnosis. Patients with levels above this threshold survived a median of 75 months, or more than six years, and had a significantly higher body mass index (a measure of body fat based on weight and height) than the group with lower plasma FGF21 levels..
Though these results support FGF21 as a biomarker of ALS prognosis, “a limitation of our plasma FGF21 study is the small number of patients, which in a heterogeneous disorder such as ALS, can lead to premature conclusions,” the researchers cautioned.
By testing cell models in the lab, the team investigated how FGF21 may exert its protective effects. Oxidative stress (cell damage caused by oxidant molecules when they outweigh antioxidant defenses) increased FGF21 signaling in motor neurons but decreased cell survival. Exposure to more FGF21 improved survival, suggesting that increased signaling may be an attempt to protect the cell.
ALS model motor neurons exhibited lower survival rates than healthy cells. However, FGF21 exposure could still increase survival back to control levels. Additionally, exposure to FGF21 promoted muscle cell growth.
“In summary, we have identified FGF21 as a novel biomarker in ALS that is detected in multiple compartments including muscle, spinal cord, and circulation,” the researchers wrote. “It is strongly expressed in atrophied [muscle fibers], and high plasma levels associated with slower disease progression.”
Due to the study’s small size and limitations of cellular models, further work will be necessary to test this hypothesis, the researchers said. “Future studies will need to test FGF21 [in ALS animal models] … to assess its potential as a novel therapy in ALS,” the team wrote. “Plasma FGF21 levels might have value as a prognostic biomarker but will need validation in larger multi-center studies.”
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