Wnt antagonist FRZB is a muscle biomarker of denervation atrophy in amyotrophic lateral sclerosis

Abstract Skeletal muscle and the neuromuscular junction are the earliest sites to manifest pathological changes in amyotrophic lateral sclerosis (ALS). Based on prior studies, we have identified a molecular signature in muscle that develops early in ALS and parallels disease progression. This signat...

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Autores principales:	Thaddaeus Kwan, Mohamed Kazamel, Kristina Thoenes, Ying Si, Nan Jiang, Peter H. King
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5818ae8790184c18a4eb0a039ecf46e0
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spelling	oai:doaj.org-article:5818ae8790184c18a4eb0a039ecf46e02021-12-02T18:37:07ZWnt antagonist FRZB is a muscle biomarker of denervation atrophy in amyotrophic lateral sclerosis10.1038/s41598-020-73845-z2045-2322https://doaj.org/article/5818ae8790184c18a4eb0a039ecf46e02020-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-73845-zhttps://doaj.org/toc/2045-2322Abstract Skeletal muscle and the neuromuscular junction are the earliest sites to manifest pathological changes in amyotrophic lateral sclerosis (ALS). Based on prior studies, we have identified a molecular signature in muscle that develops early in ALS and parallels disease progression. This signature represents an intersection of signaling pathways including Smads, TGF-β, and vitamin D. Here, we show that the Wnt antagonist, Frizzled Related Protein (FRZB), was increased in ALS muscle samples and to a variable extent other denervating disease but only minimally in acquired myopathies. In the SOD1G93A mouse, FRZB was upregulated in the early stages of disease (between 40 and 60 days) until end-stage. By immunohistochemistry, FRZB was predominantly localized to endomysial connective tissue and to a lesser extent muscle membrane. There was a significant increase in immunoreactivity surrounding atrophied myofibers. Because FRZB is a Wnt antagonist, we assessed β-catenin, the canonical transducer of Wnt signaling, and found increased levels mainly at the muscle membrane. In summary, we show that FRZB is part of a molecular signature of muscle denervation that may reflect disease progression in ALS. Our findings open up avenues for future investigation as to what roles FRZB and Wnt signaling might be playing in muscle denervation/reinnervation.Thaddaeus KwanMohamed KazamelKristina ThoenesYing SiNan JiangPeter H. KingNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-10 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Thaddaeus Kwan Mohamed Kazamel Kristina Thoenes Ying Si Nan Jiang Peter H. King Wnt antagonist FRZB is a muscle biomarker of denervation atrophy in amyotrophic lateral sclerosis
description	Abstract Skeletal muscle and the neuromuscular junction are the earliest sites to manifest pathological changes in amyotrophic lateral sclerosis (ALS). Based on prior studies, we have identified a molecular signature in muscle that develops early in ALS and parallels disease progression. This signature represents an intersection of signaling pathways including Smads, TGF-β, and vitamin D. Here, we show that the Wnt antagonist, Frizzled Related Protein (FRZB), was increased in ALS muscle samples and to a variable extent other denervating disease but only minimally in acquired myopathies. In the SOD1G93A mouse, FRZB was upregulated in the early stages of disease (between 40 and 60 days) until end-stage. By immunohistochemistry, FRZB was predominantly localized to endomysial connective tissue and to a lesser extent muscle membrane. There was a significant increase in immunoreactivity surrounding atrophied myofibers. Because FRZB is a Wnt antagonist, we assessed β-catenin, the canonical transducer of Wnt signaling, and found increased levels mainly at the muscle membrane. In summary, we show that FRZB is part of a molecular signature of muscle denervation that may reflect disease progression in ALS. Our findings open up avenues for future investigation as to what roles FRZB and Wnt signaling might be playing in muscle denervation/reinnervation.
format	article
author	Thaddaeus Kwan Mohamed Kazamel Kristina Thoenes Ying Si Nan Jiang Peter H. King
author_facet	Thaddaeus Kwan Mohamed Kazamel Kristina Thoenes Ying Si Nan Jiang Peter H. King
author_sort	Thaddaeus Kwan
title	Wnt antagonist FRZB is a muscle biomarker of denervation atrophy in amyotrophic lateral sclerosis
title_short	Wnt antagonist FRZB is a muscle biomarker of denervation atrophy in amyotrophic lateral sclerosis
title_full	Wnt antagonist FRZB is a muscle biomarker of denervation atrophy in amyotrophic lateral sclerosis
title_fullStr	Wnt antagonist FRZB is a muscle biomarker of denervation atrophy in amyotrophic lateral sclerosis
title_full_unstemmed	Wnt antagonist FRZB is a muscle biomarker of denervation atrophy in amyotrophic lateral sclerosis
title_sort	wnt antagonist frzb is a muscle biomarker of denervation atrophy in amyotrophic lateral sclerosis
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/5818ae8790184c18a4eb0a039ecf46e0
work_keys_str_mv	AT thaddaeuskwan wntantagonistfrzbisamusclebiomarkerofdenervationatrophyinamyotrophiclateralsclerosis AT mohamedkazamel wntantagonistfrzbisamusclebiomarkerofdenervationatrophyinamyotrophiclateralsclerosis AT kristinathoenes wntantagonistfrzbisamusclebiomarkerofdenervationatrophyinamyotrophiclateralsclerosis AT yingsi wntantagonistfrzbisamusclebiomarkerofdenervationatrophyinamyotrophiclateralsclerosis AT nanjiang wntantagonistfrzbisamusclebiomarkerofdenervationatrophyinamyotrophiclateralsclerosis AT peterhking wntantagonistfrzbisamusclebiomarkerofdenervationatrophyinamyotrophiclateralsclerosis
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Wnt antagonist FRZB is a muscle biomarker of denervation atrophy in amyotrophic lateral sclerosis

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