FGF23, a novel muscle biomarker detected in the early stages of ALS

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.

Transcriptomic analysis of human ALS skeletal muscle reveals a disease-specific pattern of dysregulated circRNAs

“…Although molecular and mitochondrial changes in skeletal muscle occur as early as 40 days post-natal [56,57], the early appearance of these circRNAs indicates that they are part of a molecular program initiated close to the onset disease. Two of these upregulated circRNAs, circ_0007099 and circ_0005171, increased with age, suggesting the possibility that they are muscle markers of disease progression as we have previously observed with members of the SMAD family, CYP27B1, FRZB, FGF23, and TGF-β1, 2, and 3 [16,[18][19][20][21]. One circRNA, circ_0000119, increased in the ES stage but remained stably increased in the LS stage.…”

“…This limitation may reflect the relative low abundance of circRNAs (compared to microRNAs for example) or methodological limitations in measuring circRNAs in the blood. The other possibility is that the circRNAs remain intracellular or are trapped in the neuromuscular space, as we postulated previously for other ALS muscle biomarkers [ 16 , 19 ].…”

“…These observations are primarily based on temporal patterns in the SOD1 G93A mouse, a model that recapitulates many but not all pathological features of classic ALS [55]. In our prior work, molecular markers identified in human ALS muscle samples by RNA-seq analysis [18] have remarkable overlap with skeletal muscle from the SOD1 G93A mouse, suggesting that molecular changes in the peripheral neuromuscular system in ALS represent a common pathway after the degenerative process has been triggered [16][17][18][19][20][21]. Our findings in this report support this possibility, as there was considerable overlap in the pattern of altered circRNAs in human and mouse ALS muscle and spinal cord tissues (Table 4).…”

“…Thus, aberrant communication at the NMJ may represent a common pathway in ALS disease progression independent of the initial trigger. In support of this hypothesis, we have identified an extensive program of altered molecular markers in skeletal muscle, including transforming growth factor beta 1 (TGF-β1) and mothers against decapentaplegic homolog 8 (SMAD8), that are consistently increased across a broad sampling of ALS patients [16][17][18][19][20][21]. The similarity of this pattern in skeletal muscle of the superoxide dismutase 1 G93A mutant (SOD1 G93A ) mouse further underscores this hypothesis, as mutations in the SOD1 gene locus represent only ~2% of all ALS [22].…”

Oncostatin M is a regulator of fibroblast growth factor 23 (FGF23) in UMR106 osteoblast-like cells

“…Apart from endocrine, bone-derived FGF23, other sources of FGF23 have been described including heart 11 , liver 12 , or kidney 13 . Extraosseous FGF23 may, at least in part, be effective under pathophysiological conditions and also induce paracrine effects 14 – 19 .…”