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.