Collagen type VI regulates TGFβ bioavailability in skeletal muscle.

Autor:	Mohassel P; National Institutes of Health, National Institute of Neurological Disorders and Stroke, Neuromuscular and Neurogenetic Disorders of Childhood Section, Bethesda, MD, USA.; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Rooney J; National Institutes of Health, National Institute of Neurological Disorders and Stroke, Neuromuscular and Neurogenetic Disorders of Childhood Section, Bethesda, MD, USA., Zou Y; National Institutes of Health, National Institute of Neurological Disorders and Stroke, Neuromuscular and Neurogenetic Disorders of Childhood Section, Bethesda, MD, USA., Johnson K; Bioinformatics Section, Intramural Information Technology & Bioinformatics Program, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA., Norato G; Clinical Trials Unit, National Institutes of Health, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA., Hearn H; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Nalls MA; National Institutes of Health, National Institute of Neurological Disorders and Stroke, Neuromuscular and Neurogenetic Disorders of Childhood Section, Bethesda, MD, USA., Yun P; National Institutes of Health, National Institute of Neurological Disorders and Stroke, Neuromuscular and Neurogenetic Disorders of Childhood Section, Bethesda, MD, USA., Ogata T; National Institutes of Health, National Institute of Neurological Disorders and Stroke, Neuromuscular and Neurogenetic Disorders of Childhood Section, Bethesda, MD, USA., Silverstein S; National Institutes of Health, National Institute of Neurological Disorders and Stroke, Neuromuscular and Neurogenetic Disorders of Childhood Section, Bethesda, MD, USA., Sleboda DA; Department of Ecology and Evolutionary Biology, University of California, Irvine, Irvine, CA, USA., Roberts TJ; Department of Ecology and Evolutionary Biology, Brown University, Providence, RI, USA., Rifkin DB; Department of Cell Biology, New York University School of Medicine, New York, NY, USA., Bönnemann CG; National Institutes of Health, National Institute of Neurological Disorders and Stroke, Neuromuscular and Neurogenetic Disorders of Childhood Section, Bethesda, MD, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Jun 24. Date of Electronic Publication: 2023 Jun 24.
DOI:	10.1101/2023.06.22.545964
Abstrakt:	Collagen VI-related disorders ( COL6 -RDs) are a group of rare muscular dystrophies caused by pathogenic variants in collagen VI genes ( COL6A1, COL6A2 , and COL6A3 ). Collagen type VI is a heterotrimeric, microfibrillar component of the muscle extracellular matrix (ECM), predominantly secreted by resident fibroadipogenic precursor cells in skeletal muscle. The absence or mislocalizatoion of collagen VI in the ECM underlies the non-cell autonomous dysfunction and dystrophic changes in skeletal muscle with an as of yet elusive direct mechanistic link between the ECM and myofiber dysfunction. Here, we conduct a comprehensive natural history and outcome study in a novel mouse model of COL6 -RDs ( Col6a2 -/- mice) using standardized (Treat-NMD) functional, histological, and physiologic parameter. Notably, we identify a conspicuous dysregulation of the TGFβ pathway early in the disease process and propose that the collagen VI deficient matrix is not capable of regulating the dynamic TGFβ bioavailability at baseline and also in response to muscle injury. Thus, we propose a new mechanism for pathogenesis of the disease that links the ECM regulation of TGFβ with downstream skeletal muscle abnormalities, paving the way for developing and validating therapeutics that target this pathway. Competing Interests: Conflict of Interest: The authors have declared that no conflict of interest exists.
Databáze:	MEDLINE
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