AUTHOR=Nitahara-Kasahara Yuko , Posadas-Herrera Guillermo , Mizumoto Shuji , Nakamura-Takahashi Aki , Inoue Yukiko U. , Inoue Takayoshi , Nomura Yoshihiro , Takeda Shin’ichi , Yamada Shuhei , Kosho Tomoki , Okada Takashi 

TITLE=Myopathy Associated With Dermatan Sulfate-Deficient Decorin and Myostatin in Musculocontractural Ehlers-Danlos Syndrome: A Mouse Model Investigation

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=9

YEAR=2021

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.695021

DOI=10.3389/fcell.2021.695021

ISSN=2296-634X

ABSTRACT=<p><italic>Carbohydrate sulfotransferase 14</italic> (<italic>CHST14</italic>) encodes dermatan 4-<italic>O</italic>-sulfotransferase 1, a critical enzyme for dermatan sulfate (DS) biosynthesis. Musculocontractural Ehlers-Danlos syndrome (mcEDS) is associated with biallelic pathogenic variants of <italic>CHST14</italic> and is characterized by malformations and manifestations related to progressive connective tissue fragility. We identified myopathy phenotypes in <italic>Chst14</italic>-deficient mice using an mcEDS model. Decorin is a proteoglycan harboring a single glycosaminoglycan chain containing mainly DS, which are replaced with chondroitin sulfate (CS) in mcEDS patients with CHST14 deficiency. We studied the function of decorin in the skeletal muscle of <italic>Chst14</italic>-deficient mice because decorin is important for collagen-fibril assembly and has a myokine role in promoting muscle growth. Although decorin was present in the muscle perimysium of wild-type (<italic>Chst14<sup>+/+</sup></italic>) mice, decorin was distributed in the muscle perimysium as well as in the endomysium of <italic>Chst14<sup>–/–</sup></italic> mice. <italic>Chst14<sup>–/–</sup></italic> mice had small muscle fibers within the spread interstitium; however, histopathological findings indicated milder myopathy in <italic>Chst14<sup>–/–</sup></italic> mice. Myostatin, a negative regulator of protein synthesis in the muscle, was upregulated in <italic>Chst14<sup>–/–</sup></italic> mice. In the muscle of <italic>Chst14<sup>–/–</sup></italic> mice, decorin was downregulated compared to that in <italic>Chst14<sup>+/+</sup></italic> mice. <italic>Chst14<sup>–/–</sup></italic> mice showed altered cytokine/chemokine balance and increased fibrosis, suggesting low myogenic activity in DS-deficient muscle. Therefore, DS deficiency in mcEDS causes pathological localization and functional abnormalities of decorin, which causes disturbances in skeletal muscle myogenesis.</p>