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

Abstract

Carbohydrate sulfotransferase 14 (CHST14) encodes dermatan 4-O-sulfotransferase 1, a critical enzyme for dermatan sulfate (DS) biosynthesis. Musculocontractural Ehlers-Danlos syndrome (mcEDS) is associated with biallelic pathogenic variants of CHST14 and is characterized by malformations and manifestations related to progressive connective tissue fragility. We identified myopathy phenotypes in Chst14-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 Chst14-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 (Chst14+/+) mice, decorin was distributed in the muscle perimysium as well as in the endomysium of Chst14–/– mice. Chst14–/– mice had small muscle fibers within the spread interstitium; however, histopathological findings indicated milder myopathy in Chst14–/– mice. Myostatin, a negative regulator of protein synthesis in the muscle, was upregulated in Chst14–/– mice. In the muscle of Chst14–/– mice, decorin was downregulated compared to that in Chst14+/+ mice. Chst14–/– 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.

Histories of Dermatan Sulfate Epimerase and Dermatan 4-O-Sulfotransferase from Discovery of Their Enzymes and Genes to Musculocontractural Ehlers-Danlos Syndrome

“…In 2021, Nitahara-Kasahara et al demonstrated that elephant teeth, thoracic kyphosis, increased skin fragility, and a kinked tail were observed in Chst14 -/mice [135,136]. Moreover, they also found a reduction in DS disaccharide in muscle and myopathy-related phenotypes including spread of the muscle interstitium and variation in fiber size, which may lead to decreased exercise capacity and lower grip strength in Chst14 -/mice.…”

The Specific Role of Dermatan Sulfate as an Instructive Glycosaminoglycan in Tissue Development

“…DSE and CHST14 encode DSE and dermatan 4-O-sulfoteransferase (D4ST), respectively, which function to biosynthesize DS [25][26][27]. Both knockout mice exhibited similar phenotypes such as skin fragility, thoracic kyphosis, and spina bifida, to patients with EDS of the musculocontractural type [28][29][30][31][32]. Therefore, DS is an indispensable macromolecule for the normal development of various tissues.…”

“…Chst14 -/mice exhibited elephant teeth, a kinked tail, increased skin fragility, and thoracic kyphosis, compared with Chst14 +/+ mice [29,31]. Moreover, Nitahara-Kasahara et al demonstrated that decreases in DS in muscle in addition to myopathy-related phenotypes such as variation in fiber size and spread of the muscle interstitium which caused lower grip strength and decreased exercise capacity, were observed in Chst14 -/mice compared with Chst14 +/+ as well as Chst14 +/mice [31,32].…”

Alterations in glycosaminoglycan biosynthesis associated with the Ehlers-Danlos syndromes

“…(132,133) Furthermore, Chst14 -/mice showed thoracic kyphosis, and myopathy-related phenotypes such as lower grip strength and decreased exercise capacity, with decreased DS in muscle and variation in fiber size and spread of the muscle interstitium. (132,134) Additionally, Chst14 -/mice provided evidence for an overall negative impact of DS on peripheral nerve regeneration (131) but beneficial activity in central nervous system regeneration, which could result from differences in DS proteoglycans levels and their interaction partners between the peripheral and central nervous systems. ( 135) Chst14 -/mice also showed impaired spatial learning and memory and demonstrated that DS is indispensable for synaptic plasticity in the hippocampus, which might be attributed to impaired Akt/mTOR-signalling.…”