Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive muscle weakness. Skeletal muscle is a prime source for biomarker discovery since it is one of the earliest sites to manifest disease pathology. From a prior RNA sequencing project, we identified FGF23 as a potential muscle biomarker in ALS. Here, we validate this finding with a large collection of ALS muscle samples and found a 13-fold increase over normal controls. FGF23 was also increased in the SOD1G93A mouse, beginning at a very early stage and well before the onset of clinical symptoms. FGF23 levels progressively increased through end-stage in the mouse. Immunohistochemistry of ALS muscle showed prominent FGF23 immunoreactivity in the endomysial connective tissue and along the muscle membrane and was significantly higher around grouped atrophic fibers compared to non-atrophic fibers. ELISA of plasma samples from the SOD1G93A mouse showed an increase in FGF23 at end-stage whereas no increase was detected in a large cohort of ALS patients. In conclusion, FGF23 is a novel muscle biomarker in ALS and joins a molecular signature that emerges in very early preclinical stages. The early appearance of FGF23 and its progressive increase with disease progression offers a new direction for exploring the molecular basis and response to the underlying pathology of ALS.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive muscle weakness
In this report we have shown that FGF23 expression is increased in ALS muscle tissue and progressively increases with disease progression in the S OD1G93A mouse model of ALS
It is localized mainly to the endomysial connective tissue and muscle membrane, but increases are not detected in plasma samples off ALS patients
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive muscle weakness. The end-organ responsible for the progressive weakness that defines ALS, is an accessible tissue with great potential to facilitate discovery of novel biomarkers. Involvement of skeletal muscle is underscored by our prior work which defines a molecular signature in ALS skeletal muscle beginning in the earliest pre-clinical phases of disease based on correlative studies with the SOD1G93A mouse. Characterization of this signature emerged from RNA sequencing of human ALS muscle, and encompasses genes of diverse pathways including Smads, TGF-β, vitamin D (CYP27-B1), FRZB/Wnt signaling, and select microRNAs9–13. Our findings broaden the scope of potential signaling pathways in muscle that are activated early in the course of ALS through end-stage, and provide direction for the development of new treatments
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